Pyrido[2,3-d]pyrimidine-2,7-diamine kinase inhibitors

ABSTRACT

Disclosed are compounds of the formula 
                 
 
wherein R 2 , R 5 , R 6 , R 7 , and R 8  are as defined herein. These compounds and their pharmaceutical compositions are useful for treating cell proliferative disorders, such as cancer and restenosis. These compounds are potent inhibitors of cdks and growth factor-mediated kinases.

This application is a 371 application of PCT/IB01/00069 filed Jan. 23,2001, which claims the benefit of priority to U.S. provisionalapplication Ser. No. 60/178,261 filed Jan. 25, 2000.

FIELD OF THE INVENTION

This invention relates to pyrido[2,3-d]pyrimidine-2,7-diamines thatinhibit cyclin-dependent serine/threonine kinases and growthfactor-mediated tyrosine kinase enzymes and as such are useful to treatcell proliferation diseases and disorders.

BACKGROUND OF THE INVENTION

Summary of the Related Art

Cell cycle kinases are naturally occurring enzymes involved inregulation of the cell cycle (Meijer L., “Chemical Inhibitors ofCyclin-Dependent Kinases,” Progress in Cell Cycle Research, 1995;1:351-363). Typical enzymes include serine/threonine kinases such as thecyclin-dependent kinases (cdks) cdk1, cdk2, cdk4, cdk5, cdk6, as well astyrosine kinases involved in cell cycle regulation. Increased activityor temporally abnormal activation or regulation of these kinases hasbeen shown to result in development of human tumors and otherproliferative disorders. Compounds that inhibit cdks, either by blockingthe interaction between a cyclin and its kinase partner, or by bindingto and inactivating the kinase, cause inhibition of cell proliferation,and are thus useful for treating tumors or other abnormallyproliferating cells.

Several compounds that inhibit cdks have demonstrated preclinicalantitumor activity. For example, flavopiridol is a flavonoid that hasbeen shown to be a potent inhibitor of several types of breast and lungcancer cells (Kaur et al., J. Natl. Cancer Inst., 1992; 84:1736-1740;Int. J. Oncol., 1996; 9:1143-1168). The compound has been shown toinhibit cdk2 and cdk4. Olomoucine[2-(hydroxyethylamino)-6-benzylamine-9-methylpurine] is a potentinhibitor of cdk2 and cdk5 (Vesely et al., Eur. J. Biochem., 1994;224:771-786), and has been shown to inhibit proliferation ofapproximately 60 different human tumor cell lines used by the NationalCancer Institute (NCI) to screen for new cancer therapies (Abraham etal., Biology of the Cell, 1995; 83:105-120). More recently, thepurvalanol class of cdk inhibitors has emerged as more potentderivatives of olomoucine (Gray N. S. et al., Science, 1998;281:533-538).

Tyrosine kinases are essential for the propagation of growth factorsignal transduction leading to cell cycle progression, cellularproliferation, differentiation, and migration. Tyrosine kinases includecell surface growth factor receptor tyrosine kinases such as FGFr andPDGFr, as well as nonreceptor tyrosine kinases, including c-Src and lck.Inhibition of these enzymes has been demonstrated to cause antitumor andantiangiogenesis activity (Hamby et al., Pharmacol. Ther., 1999;82(2-3):169-193).

Several pyrido[2,3-d]pyrimidines that inhibit cdks and growthfactor-mediated kinase enzymes are known (WO 98/33798). U.S. Pat. Nos.5,733,913 and 5,733,914 describe 6-aryl-pyrido[2,3-d]pyrimidines.

Despite the progress that has been made, the search continues for lowmolecular weight compounds that are orally bioavailable and useful fortreating a wide variety of human tumors and other proliferativedisorders, including restenosis, angiogenesis, diabetic retinopathy,psoriasis, surgical adhesions, macular degeneration, andatherosclerosis. The present invention provides such compounds, theirpharmaceutical formulations, and their use in treating proliferativedisorders.

SUMMARY OF THE INVENTION

This invention provides novel pyrido[2,3-d]pyrimidine-2,7-diaminecompounds which function as inhibitors of cell cycle regulatory kinasessuch as the cyclin dependent kinases as well as the growthfactor-mediated tyrosine kinases. Thus, these compounds are useful totreat cell proliferative disorders such as atherosclerosis andrestenosis; cancer; angiogenesis; viral infections including DNA virusessuch as herpes and RNA viruses such as HIV; fungal infections; type 1diabetes, diabetic neuropathy and retinopathy; multiple sclerosis;glomerulonephritis; neurodegenerative diseases including Alzheimer'sdisease; autoimmune diseases such as psoriasis, rheumatoid arthritis,and lupus; organ transplant rejection and host versus graft disease;gout; polycystic kidney disease; and inflammation including inflammatorybowel disease.

Accordingly, the present invention provides pyrido[2,3-d]pyrimidinehaving the generic structure of Formula I

wherein:

-   R², R⁷, R¹³, R¹⁴ and R¹⁵ are independently hydrogen, or    -   lower alkyl, lower alkenyl, or lower alkynyl, each of which is        optionally substituted with up to 5 groups independently        selected from halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹,        —(CH₂)_(n)CO₂R⁹, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹, —COR⁹,        —CONR⁹R¹⁰, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰,        —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰,        —NR⁹SO₂R¹⁰, or        -   a heterocycle optionally substituted with up to 3 groups            independently selected from —R⁹, —NR⁹R¹⁰, —OR⁹, —NR⁹COR¹⁰,            —COR¹⁰, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹, or    -   —(CH₂)_(n)R¹² optionally substituted with up to 5 groups        independently selected from halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰,        —OR⁹, —(CH₂)_(n)CO₂R⁹, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹, —COR⁹,        —CONR⁹R¹⁰, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰,        —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰,        —NR⁹SO₂R¹⁰, or        -   a heterocycle optionally substituted with up to 3 groups            independently selected from —R⁹, —NR⁹R¹⁰, —OR⁹, —NR⁹COR¹⁰,            —COR¹⁰, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹;-   R⁵ is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, or —OR⁹;-   R⁶ is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹, —CO₂R⁹, —COR⁹,    —CONR⁹R¹⁰, —NR⁹COR¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SO₃R⁹, —SR⁹, —PO₃R⁹R¹⁰,    —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, or    -   lower alkenyl or lower alkynyl optionally substituted with —R⁹;-   R⁸ is H, —CO₂R¹³, —COR¹³, —CONR¹³R¹⁴, —CSNR¹³R¹⁴, —C(NR¹³)NR¹⁴R¹⁵,    —SO₃R¹³, —SO₂R¹³, —SO₂NR¹³R¹⁴, —PO₃ ¹³R¹⁴, —POR¹³R¹⁴, —PO(NR¹³R¹⁴)₂;-   R⁹ and R¹⁰ are independently hydrogen, or    -   lower alkyl, optionally substituted with up to 3 groups selected        from the group consisting of halogen, amino, mono- or        dialkylamino, hydroxy, lower alkoxy, phenyl or substituted        phenyl,    -   or when taken together with the nitrogen to which they are        attached, R⁹ and R¹⁰ form a ring having from 3-7 members, up to        four of which may be selected from        O, S, and NR²⁰, where R²⁰ is hydrogen, lower alkyl, or —CO lower        alkyl;-   R¹¹ is a heteroaryl or a heterocyclic group;-   R¹² is a cycloalkyl, a heterocyclic, an aryl, or a heteroaryl group;-   n is 0, 1, 2, or 3;    and the pharmaceutically acceptable salts, esters, amides, and    prodrugs thereof.

The present invention also provides a composition that comprises acompound of Formula I together with a pharmaceutically acceptablecarrier, diluent, or excipient.

The present invention also provides methods for inhibitingcyclin-dependent kinase and growth factor-mediated kinase enzymes.

The present invention also provides a method of treating subjectssuffering from diseases caused by cellular proliferation. The methodcomprises inhibiting proliferation of tumorigenic cells of epithelialorigin and vascular smooth muscle proliferation and/or cellularmigration by administering a therapeutically effective amount of acompound of Formula I to a subject in need of treatment.

The present invention also provides a method of treating subjectssuffering from diseases caused by DNA tumor viruses, such as herpesviruses comprising administering a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The compounds encompassed by the instant invention are those describedby the general Formula I set forth above, and the pharmaceuticallyacceptable salts, esters, amides, and prodrugs thereof.

In addition to the compounds of Formula I, the invention providespreferred compounds of Formula II:

wherein R⁵, R⁶, R⁷, and R⁸ are as defined above for Formula I;

-   R¹⁶, R¹⁷, and R¹⁸ are as defined above for the (CH₂)_(n)R¹²    substituents, and preferably are independently hydrogen, halogen,    amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy,    cyano, nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- or    dialkylaminocarbonyl, alkylcarbonyl, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹,    —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰,    —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰; or-   R¹⁶ is a carbocyclic group containing from 3-7 members, up to 2 of    which members are heteroatoms selected from oxygen and nitrogen,    wherein the carbocyclic group is unsubstituted or substituted with    1, 2, or 3 groups as defined above, but preferably are independently    selected from the group consisting of halogen, hydroxy, lower alkyl,    trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl,    heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl,    heteroarylsulfonylalkly, heterocyclylalkyl, heterocyclylsulfonyl, or    heterocyclylsulfonylalkyl.

Preferred compounds of Formula II are where R⁵ is hydrogen or loweralkyl; R⁶ is hydrogen, lower alkyl, cyano or halogen; R¹⁷ and R¹⁸ areindependently hydrogen, halogen, amino, mono- or dialkylamino, hydroxy,lower alkyl, lower alkoxy, aminocarbonyl, mono- or dialkylaminocarbonyl,—SO₂NR⁹R¹⁰ or —NR⁹COR¹⁰; and R¹⁶ is optionally substituted N-piperidine,N-piperazine, or N-pyrrolidine, for instance where the ring substituentsare selected from —R⁹, —NR⁹R¹⁰, —OR⁹, NR⁹COR¹⁰, and COR¹⁰.

In addition, the present invention also provides preferred compounds ofFormula III:

wherein R², R⁵, and R⁶ are as defined above for Formula I; and

-   R¹⁹ is hydrogen, or    -   lower alkyl, lower alkenyl, or lower alkynyl, each of which is        optionally substituted with up to 5 groups independently        selected from halogen, amino, mono- or dialkylamino, hydroxy,        lower alkoxy, cyano, nitro, carboxy, carboxyalkyl,        aminocarbonyl, mono- or dialkylaminocarbonyl, lower        alkylcarbonyl, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰,        —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰,        —NR⁹SO₂R¹⁰, where R⁹ and R¹⁰ are as defined above, or    -   aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or        cycloalkyl-alkyl, where each aryl, heteroaryl or cycloalkyl        group is optionally substituted with up to 5 groups        independently selected from halogen, amino, mono- or        dialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy,        carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl,        alkylcarbonyl, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰,        —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰,        —NR⁹SO₂R¹⁰, or    -   a (CH₂)_(n)-carbocyclic group containing from 3-7 members, up to        2 of which members are heteroatoms selected from oxygen and        nitrogen, wherein the carbocyclic group is unsubstituted or        substituted with 1, 2, or 3 groups independently selected from        the group consisting of halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino,        aryl, heteroaryl, arylalkyl, heteroarylalkyl,        heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl,        heterocyclylsulfonyl, or heterocyclylsulfonylalkyl; and    -   R²¹ is hydrogen, lower alkyl, or lower alkyl substituted with        phenyl or substituted phenyl.

Preferred compounds of Formula III are where R⁵ is hydrogen or loweralkyl, R⁶ is hydrogen or halogen, R² is optionally substituted phenyl;R²¹ is hydrogen or methyl; and R¹⁹ is optionally substituted loweralkyl, cycloalkyl, or (CH₂)_(n)-carbocyclic.

An especially preferred group of pyrido[2,3-d]pyrimidines have FormulaIV:

wherein R⁵, R⁶, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²¹ are as defined above.Preferred compounds of Formula IV are those wherein R²¹ is hydrogen ormethyl.

Another especially preferred group of invention compounds have FormulaV:

wherein R⁵, R⁶, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²¹ are as defined above.Preferred compounds of Formula V are those wherein R²¹ is hydrogen ormethyl.

The most preferred invention compounds have Formula VI

wherein R⁵, R⁶, R¹⁷, and R¹⁸ are as defined above, and R²² and R²³independently are hydrogen or alkyl.

By “alkyl,” “lower alkyl,” and “(C₁-C₁₀)-alkyl” in the present inventionis meant straight or branched chain alkyl groups having 1 to 10 carbonatoms, preferably C₁-C₆ alkyl. Typically alkyl groups include methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, decyl, octyl,and 3-methylpentyl. These groups may be substituted, for instance withhalo, C₁-C₃ alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy, andthe like. Examples include chloromethyl, 2-amino-ethyl, and3-dimethyl-aminopropyl.

By “alkenyl,” “lower alkenyl,” and (C₂-C₁₀)-alkenyl is meant straight orbranched chain alkyl groups having 1 to 10 carbon atoms and having 1 or2 nonadjacent double bonds. Examples of alkenyls include, but are notlimited to, 3-butenyl and 1-methyl-3-pentenyl.

By “alkynyl,” “lower alkynyl,” and (C₂-C₁₀)-alkynyl is meant straight orbranched chain alkyl groups having 1 to 10 carbon atoms and having atriple bond. Typical alkynyl groups include 2-propynyl and1,1-dimethyl-3-butynyl. Substituted alkenyl and alkynyl groups include4,4-dibromo-2-pentenyl and 3-amino-5-hexynyl.

By “alkoxy,” “lower alkoxy,” or “(C₁-C₁₀)-alkoxy” in the presentinvention is meant straight or branched chain alkoxy groups having 1 to10 carbon atoms, such as, for example, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

The term “alkanoyl” means an alkyl group bonded through a carbonylmoiety. Examples include acetyl and pentanoyl. “Aminoalkanoyl” means thealkyl group is substituted with an amino group. Examples includeaminoacetyl and 3-aminohexanoyl. “Alkylaminoalkanoyl” means anaminoalkanoyl group wherein the amine is substituted with a C₁-C₁₀ alkylgroup, and includes methylaminoacetyl and 4-(isobutylamino)-octanoyl.“Dialkylaminoalkanoyl” means an N,N-di-substituted aminoalkanoyl groupsuch as diisopropylaminoacetyl.

By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

The term “aryl” means an unsubstituted aromatic carbocyclic group havinga single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl). The term“substituted aryl” means an aryl substituted by 1 to 4 substituentsselected from alkyl, O-alkyl and S-alkyl, —OH, —SH, —CN, halo,1,3-dioxolanyl, —CF₃, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCO-alkyl,—(CH₂)_(m)CO₂H, —(CH₂)_(m)CO₂-alkyl, —(CH₂)_(m)SO₃H, —NH alkyl,—N(alkyl)₂, —(CH₂)_(m)PO₃H₂, —(CH₂)_(m)PO₃(alkyl)₂, —(CH₂)_(m)SO₂NH₂,and —(CH₂)_(m)SO₂NH-alkyl, wherein alkyl is defined as above and m is 0,1, 2, or 3. Some examples of substituted aryl groups are methylphenyl,isopropoxyphenyl, chlorophenyl,2-bromo-3-trifluoromethyl-4-nitro-5-aminophenyl, 4-bromobiphenyl,3-acetamidonaphthyl, 3-dimethylaminoanthryl, 3,4-dimethoxyphenanthryl,and 2,8-dibromobiphenylen-1-yl.

By “heteroaryl” is meant one or more aromatic ring systems of 5-, 6-, or7-members containing at least 1 and up to 4 heteroatoms selected fromnitrogen, oxygen, or sulfur. Such heteroaryl groups include, forexample, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl,tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, (iso)quinolinyl,napthyridinyl, phthalimidyl, benzimidazolyl, benzoxazolyl. A“substituted heteroaryl” group can be substituted with 1, 2, 3, or 4 ofthe groups mentioned above for “substituted aryl,” such as2,3,4,6-tetrachloropyridyl and 2-methoxy-3-trifluoromethylthien-4-yl.

The term “heterocyclic group” means a non-aromatic ring having 5-, 6-,or 7-ring atoms, from 1 to 4 of which are selected from nitrogen,oxygen, or sulfur. Examples of heterocyclic groups include morpholino,piperidino, piperazino, pyrrolidinyl, and tetrahydrothienyl. Such groupscan be substituted with the same groups described above for substitutedheteroaryl.

A “carbocyclic group” or “cycloalkyl” is a nonaromatic cyclic ring orfused rings having from 3- to 7-ring carbon members. Examples includecyclopropyl, cyclobutyl, and cycloheptyl. These rings may be substitutedwith one or more of the substituent groups mentioned above for aryl, forexample alkyl, halo, amino, hydroxy, and alkoxy. Typical substitutedcarbocyclic groups include 2-chlorocyclopropyl, 2,3-diethoxycyclopentyl,and 2,2,4,4-tetrafluorocyclohexyl. The carbocyclic group may contain 1or 2 heteroatoms selected from oxygen, sulfur, and nitrogen, and suchring systems are referred to as “heterocyclyl” or “heterocyclic”.Examples include piperidyl, piperazinyl, pyrrolidinyl, pyranyl,tetrahydrofuranyl, and dioxanyl. These heterocyclyl groups may besubstituted with up to 4 of the substituent groups mentioned for aryl togive groups such as 3,5-dimethylpiperazin-1-yl,3,3-diethylpiperazin-1-yl, 3,3,4,4-tetramethylpyrrolidinyl,3-chloro-2-dioxanyl, and 3,5-dihydroxymorpholino. These can also bear aketo group, for instance, 3-ketopiperidyl.

The term “cancer” includes, but is not limited to, the following tumortypes: breast, ovary, cervix, prostate, testis, esophagus, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, adenocarcinoma, bone, colon, adenoma,pancreas, thyroid, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma,liver carcinoma and biliary passages, kidney carcinoma, myeloiddisorders, lymphoid disorders, Hodgkin's, hairy cell carcinoma, cancerof the buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx,small intestine, colon, rectum, large intestine, brain and centralnervous system; and leukemia.

The compounds of Formulas I to VI can exist as pharmaceuticallyacceptable salts, esters, amides, and prodrugs. The term“pharmaceutically acceptable salts, esters, amides, and products” asused herein refers to those carboxylate salts, amino acid additionsalts, esters, amides, and prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. The term “salts” refers to the relatively nontoxic,inorganic, and organic acid addition salts and base salts of compoundsof the above formulas. These salts can be prepared in situ during thefinal isolation and purification of the compounds, or by separatelyreacting the purified compound in its free base form, for example, witha suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylatemesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, andthe like. When the compound of the above formulas has one or more acidicgroups, it can form a salt by reaction with a base. These salts mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asinorganic bases such as ammonium, quaternary ammonium, and other aminecations including, tetramethylammonium, tetraethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.Pharmaceutically acceptable salts are well-known to those skilled in theart of medicinal chemistry. (See, for example, Berge S. M. et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19 which isincorporated herein by reference.)

Examples of pharmaceutically acceptable, nontoxic esters of thecompounds of this invention include C₁-C₆ alkyl esters, wherein thealkyl group is a straight or branched hydrocarbon, substituted orunsubstituted. Esters also include C₅-C₇ cycloalkyl esters, as well asarylalkyl esters such as benzyl and triphenylmethyl, C₁-C₄ Alkyl estersare preferred, such as methyl, ethyl, 2,2,2-trichloroethyl, andtert-butyl. Esters of the compounds of the present invention may beprepared according to conventional methods, for example by reaction ofan acid with an alcohol.

Examples of pharmaceutically acceptable amides of the compounds of thisinvention include amides derived from ammonia, primary C₁-C₆ alkylamines and secondary C₁-C₆ dialkyl amines, wherein the alkyl groups arestraight or branched. In the case of secondary amines, the amine mayalso be in the form of a 5- or 6-membered heterocycle containing 1nitrogen atom. Amides derived from ammonia, C₁-C₃ alkyl primary amines,and C₁-C₂ dialkyl secondary amines are preferred. Amides of thecompounds of the invention may be prepared according to conventionalmethods well-known to the medicinal chemists.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood or stomach fluids. A thorough discussion of prodrugsis provided by Higuchi T. and Stella V., “Pro-drugs as Novel DeliverySystems,” Vol. 14 of the A.C.S. Symposium Series, and in BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are herebyincorporated by reference.

Representative compounds of the invention are shown below in Table 1.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to, the compounds in Table 1and their pharmaceutically acceptable acid or base addition salts, esteror amide analogs, and prodrugs thereof.

The compounds of the present invention can exist in unsolvated forms aswell as solvated forms, including hydrated forms. In general, thesolvated forms, including hydrated forms, are equivalent to unsolvatedforms and are intended to be encompassed within the scope of the presentinvention.

Some of the compounds of Formula I have one or more chiral centers, andcan thus exist as individual stereoisomers and mixtures thereof. Othercompounds can exist in more than one geometric form. This inventionincludes all optical and geometric isomers and forms, and mixturesthereof. Racemic mixtures of invention compounds are readily resolvedinto individual isomers by routine methods such as chromatography,fractional crystallization, and classical resolution using opticallyactive acids and salts. The individual isomers can also be prepared bychiral synthesis, including chiral hydrogenations and the like usingcommercially available chiral catalysts.

The compounds of the present invention are useful for treating cancer(for example, leukemia, and cancer of the lung, breast, prostate, andskin such as melanoma) and other proliferative diseases, including, butnot limited to, psoriasis, HSV, HIV, restenosis, and atherosclerosis. Toutilize a compound of the present invention to treat cancer, a patienthaving cancer is administered a therapeutically effective amount of apharmaceutically acceptable composition comprising an inventioncompound.

A further embodiment of this invention is a method of treating patientssuffering from diseases caused by vascular smooth muscle cellproliferation. Compounds within the scope of the present inventioneffectively inhibit vascular smooth muscle cell proliferation andmigration. The method entails inhibiting vascular smooth muscleproliferation, and/or migration by administering an effective amount ofa compound of Formulas I to VI to a subject in need of treatment.“Subject” and “patient”, as used herein, is a mammal such as a human,but also includes horses, cattle, sheep, and companion animals such asdogs and cats.

The compounds of the present invention can be formulated andadministered in a wide variety of oral and parenteral dosage forms,including transdermal and rectal administration. It will be recognizedto those skilled in the art that the following dosage forms may compriseas the active component, either a compound of Formula I or acorresponding pharmaceutically acceptable salt or solvate of a compoundof Formula I.

A further embodiment of this invention is a pharmaceutical compositioncomprising a compound of Formulas I to VI together with apharmaceutically acceptable carrier, diluent, or excipient therefor. Forpreparing pharmaceutical compositions with the compounds of the presentinvention, pharmaceutically acceptable carriers can be either a solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispensable granules. A solidcarrier can be one or more substances which may also act as diluents,flavoring agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material.

In powders the carrier is a finely divided solid such as talc or starchwhich is in a mixture with the finely divided active component. Intablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The formulations of this invention preferably contain from about 5% toabout 70% or more of the active compound. Suitable carriers includemagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like. Apreferred form for oral use are capsules, which include the formulationof the active compound with encapsulating material as a carrierproviding a capsule in which the active component with or without othercarriers, is surrounded by a carrier, which is thus in association withit. Similarly, cachets and lozenges are included. Tablets, powderscapsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted, and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient size molds, allowed tocool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsionssuch as water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution, isotonic saline, 5% aqueous glucose, andthe like. Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizing and thickening agents as desired. Aqueoussuspensions suitable for oral use can be made by dispersing the finelydivided active component in water and mixing with a viscous material,such as natural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like. Waxes, polymers, microparticles, and the like can be utilizedto prepare sustained-release dosage forms. Also, osmotic pumps can beemployed to deliver the active compound uniformly over a prolongedperiod.

The pharmaceutical preparations of the invention are preferably in unitdosage form. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

The therapeutically effective dose of a compound of Formula I willgenerally be from about 1 to about 100 mg/kg of body weight per day.Typical adult doses will be about 50 to about 800 mg per day. Thequantity of active component in a unit dose preparation may be varied oradjusted from about 0.1 to about 500 mg, preferably about 0.5 to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents. A subject in need of treatment with acompound of Formula I is administered a dosage of about 1 to about 500mg per day, either singly or in multiple doses over a 24-hour period.

The compounds of the present invention are capable of binding to andinhibiting the activity of proteins having the ability to phosphorylateother proteins, such as cdks, PDGFr, FGFr, c-Src, and EGFr. Cdks formcomplexes with cyclins, and these complexes phosphorylate key proteinsallowing cells to proceed through the cell cycle (Meijer L., Progress inCell Cycle Research, 1995; 1:351-363). The compounds of this inventioninhibit this phosphorylation and therefore can be used asanti-proliferative agents for the treatment of cancer and/or restenosisand other proliferative diseases.

Because of their inhibitor activity against cdks and other kinases, thecompounds of the present invention are also useful research tools forstudying the mechanism of action of those kinases, both in vitro and invivo.

The preparation and use of the compounds of this invention are furtherdescribed in the following detailed example. The examples are intendedto illustrate particular embodiments of the invention, and are notintended to limit the scope of the specification or the claims in anyway. The invention compounds are prepared by synthetic methodologieswell-known to those skilled in the art of organic chemistry, and utilizecommercially available starting materials and reagents.

It may be desirable during the synthesis of an invention compound toderivatize reactive functional groups in the molecule undergoingreaction so as to avoid unwanted side reactions. Functional groups suchas hydroxy, amino, and acid groups typically are protected with suitablegroups that can be readily removed when desired. Use of commonprotecting groups is described fully by Green and Wuts in ProtectiveGroups in Organic Synthesis, John Wiley and Sons, New York, N.Y. (2^(nd)Edition, 1991). Typical hydroxy protecting groups include ether forminggroups such as benzyl, and aryl groups such as tert-butoxycarbonyl(Boc), formyl, and acetyl. Amino protecting groups include benzyl, arylsuch as acetyl, and trialkylsilyl groups. Carboxylic acid groupstypically are protected by conversion to an ester that can be easilyhydrolyzed, for example, trichloroethyl, tert-butyl, benzyl, and thelike.

As noted above, some of the invention compounds have one or more chiralcenters, and thus can exist as individual optical isomers and geometricisomers, and mixtures thereof. Compound 106, for example, has twoasymmetric centers, and has the cis configuration. This inventionincludes all such geometric isomers, enantiomers and RS racemates, aswell as the individual R or S isomers of chiral compounds. Allindividual isomers and mixtures thereof are included in this invention.Individual isomers are readily prepared by a chiral synthesis or byconventional resolution techniques well-known to those skilled in theart.

An illustration of the preparation of compounds of the present inventionis shown in Schemes 1-4. The synthesis of Compound 1 (Example 15) isdepicted in Scheme 1; however, it should be recognized that the generalscheme is applicable to all of the invention compounds. Each step shownin the Schemes is further illustrated in the detailed examples thatfollow.

In Scheme 1, a 2-methylthio-4-halo-5-alkoxycarbonylpyrimidine is reactedwith ammonium hydroxide to give the corresponding 4-amino derivative.The ester is reduced by reaction by reaction with LiAlH₄ to give the5-hydroxymethyl analog, which in turn is oxidized to a 5-formylderivative. The 5-formyl group is converted to an unsaturated (acrylate)group, which is cyclized to form a pyrido[2,3-d]pyrimidine. Thepyridopyrimidine is converted to a key intermediate, namely2-methylsulfanyl-pyrido[2,3-d]pyrimidine-7-ylamine, which is readilyoxidized to give a 2-methylsulfinyl analog. The 2-methylsulfinyl groupis easily displaced by reaction with an amine R₂NH₂ to provide theinvention compounds of Formula I. The 7-amino group on thepyridopyrimidine ring is readily converted to a urea by reaction with anisocyanate such as R¹⁹N═C═O.

The reactants shown in Scheme 1 have the following meanings: (a) NH₃;(b) LAH; (c) MnO₂; (d) Ph₃PCHCO₂Et; (e) DBU; (f) POCl₃; (g) NH₃; (h)(±)-Trans-2-(phenylsulfonyl)-3-phenyloxaziridine; (i)4-(4-Boc-piperidine)aniline; (j) NaH, t-Butylisocyanate; (k) HCl

Scheme 2 illustrates an alternative synthesis of pyridopyrimidine havinga urea functionality at the 7-position. Whereas such ureas were preparedin Scheme 1 by reaction of an isocyanate with a7-amino-pyridopyrimidine. Scheme 2 utilizes carbonyldiimidazole toprovide an intermediate imidazolide. The imidazolide readily reacts withan amine R¹⁹NH₂ to give the corresponding urea. Scheme 2 illustratesthis process by showing the synthesis of Compound 51, and is more fullydescribed in Example 32.

Conditions: (a) NaH, Carbonyldiimidazole; (b) Cyclopentylamine; (c) HCl

Compounds of Formula I may also be prepared according to Scheme 3,wherein the synthesis of compound 4 (Example 45) is depicted.4-Amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde is reacted withmethyl magnesium bromide to give the corresponding5-(2-hydroxyethyl)-pyrimidine. The alcohol is oxidized to give themethyl ketone analog. The methyl ketone is reacted with diethylcyanomethyl phosphonate and cyclized to a5-methyl-7-amino-pyridopyrimidine. Further reaction as in Schemes 1 or 2gives invention compounds such as compound 4.

Conditions: (a) MeMgBr; (b) MnO₂; (c) (EtO)₂P(O)CH₂CN

Compounds of Formula I may also be prepared according to Scheme 4,wherein the synthesis of compound 12 (Example 40) is depicted. In thisscheme, the 2-methylthio group of a pyrimidine is first oxidized to thecorresponding methylsulfinyl analog. The methylsulfinyl group isdisplaced by reaction with an amine R²NH₂. The 5-carboxaldehyde is thenderivatized as in Scheme 1 and cyclized to give the corresponding2-(R²NH) substituted 7-amino pyridopyrimidine. The 7-amino group isarylated or otherwise derivatized as illustrated in Schemes 1-3.

Conditions: (a) (±)-Trans-2-(phenylsulfonyl)-3-phenyloxaziridine; (b)4-(4-Boc-piperidine)-aniline; (c) (EtO)₂P(O)CH₂CN

Any of the invention compounds of Formulas I-VI may be preparedaccording to Schemes 1-4, wherein the synthesis of compounds 1, 51, 4,and 12, respectively, are illustrated. Those having skill in the art oforganic chemistry will recognize that the starting materials may bevaried, and additional steps may be employed to produce compoundsencompassed by the present invention, as demonstrated by the followingspecific examples.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following detailed exampleswhich are not to be construed as limiting the invention in scope orspirit to the specific procedures described in them. The startingmaterials and various intermediates may be obtained from commercialsources, prepared from commercially available organic compounds, orprepared using well-known synthetic methods.

EXAMPLE 1 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethylester

To a room temperature solution of4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester(15.0 g, 65 mmol) in 200 mL of tetrahydrofuran is added 25 mL oftriethylamine followed by 35 mL of aqueous ammonium hydroxide. Afterstirring at room temperature for 1.5 hours, an additional 30 mL ofaqueous ammonium hydroxide is added, and stirring is continued for 1hour. The reaction mixture is concentrated in vacuo and partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic layer is washed with brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. Ethyl acetate and hexane are added,and the resultant solid is collected by filtration to provide 10.84 g(79%) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethylester.

EXAMPLE 2 (4-Amino-2-methanesulfanyl-pyrimidin-5-yl)-methanol

A solution of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxylic acidethyl ester (13.36 g, 63 mmol) in 250 mL of tetrahydrofuran is addeddropwise to a room temperature suspension of lithium aluminum hydride(3.82 g, 100 mmol) in 250 mL of tetrahydrofuran. After 30 minutes, thereaction is cooled to 0° C., and isopropyl alcohol is added untilbubbling diminishes. The reaction is quenched with 15 mL of water. 15 mLof 15% NaOH, and 50 mL of water, and the mixture is stirred for 1 hour.The white precipitate is removed by filtration and washed with ethylacetate. The filtrate is concentrated in vacuo and 3:1 hexane:ethylacetate is added. The solids are collected, washed with 3:1 hexane:ethylacetate, followed by hexane. The solid is dissolved in ethyl acetate,and the solution is dried over magnesium sulfate. Filtration followed byconcentration in vacuo gives 8.14 g (76%) of(4-amino-2-methanesulfanyl-pyrimidin-5-yl)-methanol.

Analysis calculated for C₆H₉N₃OS: C, 42.09; H, 5.30; N, 24.54. Found: C,42.31; H, 5.24; N, 24.27.

EXAMPLE 3 4-Amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde

To (4-amino-2-methanesulfanyl-pyrimidin-5-yl)-methanol (8.14 g, 48 mmol)in 1 L of chloroform is added manganese oxide (33.13 g, 381 mmol). Thesuspension is stirred at room temperature overnight then filteredthrough celite and washed with 300 mL of chloroform. The filtrate isconcentrated in vacuo to give 8.14 g (quantitative yield) of4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde, mp 185-187° C.Literature mp=183-184° C., JOC, 1958; 23:1738.

Analysis calculated for C₆H₇N₃OS: C, 42.59; H, 4.17; N, 24.83. Found: C,42.84; H 4.21; N, 24.73.

EXAMPLE 4 Ethyl 3-(4-Amino-2-methanesulfanyl-pyrimidin-5-yl)acrylate

To a room temperature solution of4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde (4.08 g, 24.14mmol) in 100 mL of tetrahydrofuran is added (carbethoxymethylene)triphenylphosphorane (10.80 g, 31 mmol). The reaction mixture is heatedat reflux for 3 hours then stirred at room temperature overnight. Thereaction mixture is concentrated in vacuo, and the residue is purifiedby flash chromatography, eluting with 1:1 ethyl acetate:hexane, toprovide 4.30 g (75%) of ethyl3-(4-amino-2-methanesulfanyl-pyrimidin-5-yl)acrylate; mp softens at 108°C.

Analysis calculated for C₁₀H₁₃N₃O₂S: C, 50.19; H, 5.48; N, 17.56. Found:C, 50.22; H, 5.45; N, 17.24.

EXAMPLE 5 2-Methanesulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

To a room temperature solution of ethyl 3-(4-amino-2-methanesulfanylpyrimidin-5-yl)acrylate (368 mg, 1.53 mmol) in 3 mL ofN,N-diisopropylethylamine is added 380 μL of1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture is heated atreflux for 3 hours then cooled to room temperature and concentrated. Theresidue is purified by flash chromatography eluting with ethyl acetate.The fractions containing the product are partially concentrated invacuo, and the solids are removed by filtration to provide 134 mg (45%)of 2-methanesulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 269-27° C.

Analysis calculated for C₈H₇N₃OS: C, 49.73; H, 3.65; N, 21.75. Found: C,49.67; H, 3.46; N, 21.49.

EXAMPLE 6 7-Chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine

A suspension of 1.0 g (5.2 mmol) of2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (Example 5) in 10 mL ofphosphorus oxychloride is heated under reflux for 1 hour. The resultingsolution is cooled and concentrated to give a solid, which is trituratedwith cold water and filtered to give 1.05 g of crude product.Recrystallization from acetonitrile lives 0.76 g (69%) of the product,mp 201-203° C.

MS (APCI) M+1: Calcd 212.0; Found 212.0.

Anal. Calcd for C₈H₆Cl₁S₁N₃: C, 45.39; H, 2.86; N, 19.85. Found: C,45.53; H, 2.90; N, 19.74.

EXAMPLE 7 2-Methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine

A suspension of 2.95 g (13.9 mmol) of7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (Example 6) in 200 mLof isopropanol saturated with ammonia is sealed and heated at 40° C. for65 hours. The suspension is resaturated with ammonia and heated foranother 18 hours at 40° C. The solid is collected by filtration andtriturated with water to give 1.98 g (74.2%) of the product, mp>250° C.

MS (APCI) M+1: Calcd 193.1; Found 193.0.

Anal. Calcd for C₈H₈N₄S₁: C, 49.98; H, 4.19; N, 29.14. Found: C, 50.14;H, 4.22; N, 29.04.

EXAMPLE 8 2-Methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine

A suspension of 10.63 g (55.3 mmol) of2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine (Example 7) in 300 mLof dichloromethane and 300 mL of methanol is treated with 18.06 g (69.1mmol) of (±)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine and stirredovernight. The suspension is filtered to remove a small amount of solid,concentrated to approximately 25 mL, and diluted with ethyl acetate. Thesolid is collected by filtration to give 9.27 g (80.5%) of the product,mp 180° C. (dec).

MS (APCI) M+1: Calcd 209.0; Found 209.1.

EXAMPLE 9 N²-Phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine

A suspension of 0.44 g (2.1 mmol) of2-methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine (Example 8) and 0.39mL (4.2 mmol) of aniline in 2 mL of dimethylsulfoxide is heated at 100°C. overnight. The resulting solution is cooled and poured into water.Ethyl acetate is added to the suspension, and the solid is collected byfiltration. The solid is purified by flash chromatography, eluting withgradient of 0% to 20% methanol/dichloromethane during 30 minutes to give0.14 g (29%) of the product, mp 255-260° C.

MS (APCI) M+1: Calcd 238.1; Found 238.1.

Anal. Calcd for C₁₃H₁₁N₅.0.18 H₂O: C, 64.92; H, 4.76; N, 29.12. Found:C, 65.26; H, 4.75; N, 28.76.

EXAMPLE 101-tert-Butyl-3-(2-phenylamino-pyrido[2,3-d]pyrimidin-7-yl)-urea

To a solution of 0.1022 g (0.431 mmol) ofN²-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine (Example 9) in 2 mL ofdimethylformamide, cooled in an ice bath, is added 0.019 g (0.47 mmol)of 60% sodium hydride. The resulting solution cooled in an ice bath, isthen treated with 0.054 mL (0.47 mmol) of tert-butyl isocyanate. Thesolution is stirred cold for 15 minutes, then at room temperature for 1hour. The solution is poured into ice-water to give a solid which iscollected by filtration and washed with hexane to give 0.0849 g (57.8%)of the product (compound 45), mp 227° C. (dec).

MS (APCI) M+1: Calcd 337.2; Found 337.1.

Anal. Calcd for C₁₈H₂₀N₆O₁.0.27 H₂O: C, 63.35; H, 6.07; N, 24.63. Found:C, 63.73; H, 5.82; N, 24.20.

EXAMPLE 11 4-(4-Nitrophenyl)-piperazine-1-carboxylic acid tert-butylester

A suspension of 7.5 g (36 mmol) of 1-(4-nitrophenyl)-piperazine and 6.94mL (40 mmol) of ethyl-diisopropyl-amine in 75 mL of dichloromethane istreated with 8.69 g (40 mmol) of di-tert-butyl dicarbonate and stirredat room temperature overnight. The resulting solution is washed withsaturated aqueous sodium bicarbonate, then with water, dried (magnesiumsulfate), and concentrated. The resulting material is purified by flashchromatography eluting with a gradient of 10% to 30% ethylacetate/hexane during 10 minutes to give 8.62 g (77.5%) of the product,mp 136-140° C.

MS (APCI) M+1: Calcd 308.2; Found 308.2.

EXAMPLE 12 4-(4-Amino-phenyl)-piperazine-1-carboxylic acid tert-butylester

To a suspension of 1.46 g (4.8 mmol) of4-(4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (Example11) and 1 g of Raney Nickel in 50 mL of tetrahydrofuran is addedhydrogen to an initial pressure of 54.5 psi. The reaction is shaken for14 hours and then filtered. The filtrate is concentrated to give 1.29 g(97%) of the product as a solid.

MS (APCI) M+1: Calcd 278.2; Found 278.2.

Anal. Calcd for C₁₅H₂₃N₃O₂: C, 64.96; H, 8.36; N, 15.15. Found: C,65.22; H, 8.58; N, 14.58.

EXAMPLE 134-[4-(7-Amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

By substituting 4-(4-amino-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (Example 12) for aniline in Example 9, 0.0744 g (36.0%)of the product is obtained, mp 219-220° C.

MS (APCI) M+1: Calcd 422.2; Found 422.2.

Anal. Calcd for C₂₂H₂₇N₇O₂.0.5 H₂O: C, 61.38; H, 6.56; N, 22.77. Found:C, 61.34; H, 6.30; N, 22.47.

EXAMPLE 144-{4-[7-(3-tert-Butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting4-[4-(7-amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (Example 13) forN²-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine in Example 10, 0.3354 g(67.9%) of the product (compound 79) is obtained, mp 225° C. (dec).

MS (APCI) M+1: Calcd 521.3; Found 521.2.

Anal. Calcd for C₂₇H₃₆N₈O₃: C, 62.29; H, 6.97; N, 21.52. Found: C,62.33; H, 6.81; N, 21.43.

EXAMPLE 151-tert-Butyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

To a suspension of 0.100 g (0.192 mmol) of4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Example 14) in 2 mL of methanol is added 2 mL of4 M hydrogen chloride/dioxane to give a solution. The suspension isstirred at room temperature overnight, then diluted with diethyl ether.The material is collected by filtration to give 0.0941 g (93.4%) of theproduct (compound 1), mp 215° C. (dec).

MS (APCI) M+1: Calcd 421.2; Found 421.1.

Anal. Calcd for C₂₂H₂₈N₈O₁.2.10 HCl.1.51 H₂O: C, 50.40; H, 6.37; N,21.37; Cl (total), 14.20. Found: C, 50.40; H, 6.18; N, 21.03; Cl(total), 14.33.

EXAMPLE 164-{4-[7-3-Cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting cyclohexyl isocyanate for tert-butyl isocyanate inExample 14, 0.1463 g (70.4%) of the product (compound 80) is obtained,mp 241° C. (dec).

MS (APCI) M+1: Calcd 547.3; Found 547.4.

Anal. Calcd for C₂₉H₃₈N₈O₃.0.28 H₂O: C, 63.13; H, 7.04; N, 20.31. Found:C, 63.14; H, 6.81; N, 20.25.

EXAMPLE 171-Cyclohexyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting4-{4-[7-(3-cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Example 16) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15, 0.0871 g (81.4%) of the product(compound 9) is obtained, mp 200° C. (dec).

MS (APCI) M+1: Calcd 447.3; Found 447.3.

Anal. Calcd for C₂₄H₃₀N₈O₁.2.55 HCl.2.82 H₂O: C, 48.83; H, 6.52; N,18.98; Cl (total), 15.31. Found: C, 48.83; H, 6.18; N, 18.89; Cl(total), 15.37.

EXAMPLE 18N²-(4-Fluoro-3-methyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine

By substituting 4-fluoro-3-methylaniline for aniline in Example 9,0.2025 g (39.2%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 270.1; Found 270.0.

EXAMPLE 191-tert-Butyl-3-[2-(4-fluoro-3-methyl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substitutingN²-(4-fluoro-3-methyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine(Example 18) for N²-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine inExample 10, 0.0656 g (47.9%) of the product (compound 46) is obtained,mp 230° C. (dec).

MS (APCI) M+1: Calcd 369.2; Found 369.1.

Anal. Calcd for C₁₉H₂₁F₁N₆O₁: C, 61.94; H, 5.75; N, 22.81. Found: C,61.82; H, 5.73; N, 22.75.

EXAMPLE 201-(4-Chloro-phenyl)-3-[2-(4-fluoro-3-methyl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting 4-chlorophenyl isocyanate for tertiary-butyl isocyanatein Example 19, 0.050 g (37%) of the product (compound 47) is obtained,mp>250° C.

MS (APCI) M+1: Calcd 423.1; Found 423.1.

Anal. Calcd for C₂₁H₁₆F₁Cl₁N₆O₁.0.23 H₂O: C, 59.07; H, 3.89; N, 19.68.Found: C, 59.09; H, 3.97; N, 19.65.

EXAMPLE 211-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea

To a suspension of 0.145 g (0.277 mmol) of1-tert-butyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(Example 15) in 5 mL of dichloromethane is added 0.19 mL (1.11 mmol) ofethyl-diisopropyl-amine. The suspension is cooled in an ice bath andtreated with 0.024 mL (0.33 mmol) of acetyl chloride. The suspension isstirred at room temperature overnight, then filtered. The solid iswashed with dichloromethane. The filtrate and washings are combined,washed with water, dried (magnesium sulfate), and concentrated. Thematerial is purified by flash chromatography eluting with a gradient of0% to 5% methanol/dichloromethane during 30 minutes to give 0.0674 g(51.8%) of the product (compound 5), mp 206-208° C. (dec).

MS (APCI) M+1: Calcd 463.3; Found 463.3.

Anal. Calcd for C₂₄H₃₀N₈O₂.0.40 H₂O: C, 61.36; H, 6.61; N, 3.85. Found:C, 61.38; H, 6.37; N, 23.98.

EXAMPLE 224-{4-[7-(3-Isopropyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting isopropyl isocyanate for tert-butyl isocyanate inExample 14, 0.909 g (69.9%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 507.3; Found 507.4.

EXAMPLE 231-Isopropyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting4-{4-[7-(3-isopropyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Example 22) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15, 0.0287 g (27.9%) of the product(compound 48) is obtained, mp 190° C. (dec).

MS (APCI) M+1: Calcd 407.2; Found 407.1.

Anal. Calcd for C₂₁H₂₆N₈O₁.2.05 TFA.0.84 H₂O: C, 46.00; H, 4.57; N,17.10. Found: C, 46.00; H, 4.65; N, 17.09.

EXAMPLE 24 Cis-3,5-dimethyl-1-(4-nitro-phenyl)-piperazine

A suspension of 6.74 g (47.8 mmol) of 4-fluoro-nitro-benzene and 10.91 g(95.5 mmol) of cis-2,6-dimethyl-piperazine is heated at 45° C. for 1hour. The reaction mixture is cooled and shaken with dichloromethane andwater. The organic layer is dried (magnesium sulfate) and concentratedto give 11.62 g (>100%) of the product as a solid.

EXAMPLE 25 Cis-2,6-dimethyl-4-(4-nitro-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

By substituting cis-3,5-dimethyl-1-(4-nitro-phenyl)-piperazine (Example24) for 1-(4-nitrophenyl)-piperazine in Example 11, 14.87 g (92.8%) ofthe product as a solid is obtained.

EXAMPLE 26

4-(4-Amino-phenyl)-cis-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester

By substitutingcis-2,6-dimethyl-4-(4-nitro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (Example 25) for4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester inExample 12, 5.03 g (64.7%) of the product as a solid is obtained.

EXAMPLE 274-[4-(7-Amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting4-(4-amino-phenyl)-cis-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester (Example 26) for aniline in Example 9, 0.6463 g (59.8%)of the product is obtained, mp 245° C. (dec).

MS (APCI) M+1: Calcd 450.3; Found 450.3.

EXAMPLE 284-{4-[7-(3-tert-Butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting4-[4-(7-amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (Example 27) forN²-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine in Example 10, 0.1828 g(74.9%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 549.3; Found 549.4.

EXAMPLE 291-tert-Butyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea

By substituting4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (Example 28) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15 is obtained 0.0910 g (92.9%) of theproduct (compound 49), mp 245° C. (dec).

MS (APCI) M+1: Calcd 449.3; Found 449.2.

EXAMPLE 304-{4-[7-(3-Cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting cyclohexyl isocyanate for tert-butyl isocyanate inExample 28, 0.1156 g (60.8%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 575.3; Found 575.3.

EXAMPLE 311-Cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea

By substituting4-{4-[7-(3-cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (Example 30) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15, 0.1022 g of the product is obtained(compound 50), mp 228° C. (dec).

MS (APCI) M+1: Calcd 475.2; Found 475.2.

EXAMPLE 324-{4-[7-(3-Cyclopentyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 0.150 g (0.36 mmol) of4-[4-(7-amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (Example 13) in 2 mL of dimethylformamide, cooledin an ice bath, is added 0.022 g (0.54 mmol) of 60% sodium hydride. Thecooled solution is stirred for 15 minutes, then treated with 0.088 g(0.54 mmol) of carbonyldiimidazole. The cooled solution is stirred foranother 30 minutes, then treated with 0.071 mL (0.72 mmol) ofcyclopentylamine. The resulting solution is stirred at room temperaturefor 1 hour, then added to cold water. The solid is collected byfiltration to give a first crop of material. The aqueous filtrate isthen extracted with dichloromethane, and the extracts are dried(magnesium sulfate) and concentrated to give a second crop of material.The 2 crops are combined and purified by flash chromatography, elutingwith a gradient of 0% to 5% methanol/dichloromethane during 30 minutesto give 0.1159 g (60.4%) of the product as a solid.

MS (APCI) M+1: Calcd 533.3; Found 533.4.

EXAMPLE 331-Cyclopentyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting4-{4-[7-(3-cyclopentyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Example 32) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15, 0.0937 g (80.8%) of the product(compound 51) is obtained, mp 210-213° C. (dec).

MS (APCI) M+1: Calcd 433.2; Found 433.2.

Anal. Calc for C₂₃H₂₈N₈O₁.2.49 HCl.1.65 H₂O.0.1 dioxane: C, 50.02; H,6.21; N, 19.94; Cl (total), 15.71. Found: C, 49.89; H, 5.81; N, 19.74;Cl (total), 14.74.

EXAMPLE 34 1-(4-Amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanol

To a suspension of 5.0 g (29 mmol)4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3) in 150mL of tetrahydrofuran, cooled by an ice bath, is added during 20minutes. 23.2 mL of a 3.0 M methylmagnesium bromide solution in diethylether (69.4 mmol). After 1 hour at 0° C. another 23.2 mL of the 3.0 Mmethylmagnesium bromide solution is added, and the suspension is allowedto come to room temperature and stirred overnight. The reaction isquenched with 100 mL of saturated aqueous ammonium chloride, andpartitioned between water and ethyl acetate. The organic layer is dried(magnesium sulfate) and concentrated to give 5.24 g (96%) of theproduct, mp 140-142° C.

MS (APCI) M+1: Calcd 186.1; Found 185.9.

EXAMPLE 35 1-(4-Amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanone

By substituting 1-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanol(Example 34) for (4-amino-2-methylsulfanyl-pyrimidin-5-yl)-methanol inExample 3 and conducting the reaction at 80° C. in toluene, 3.74 g (72%)of the product as a solid is obtained.

MS (APCI) M+1: Calcd 184.0; Found 183.9.

EXAMPLE 36 1-(4-Amino-2-methanesulfinyl-pyrimidin-5-yl)-ethanone

By substituting 1-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanone(Example 35) for 2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine inExample 8, 9.57 g (88%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 200; Found 200.

EXAMPLE 374-[4-(5-Acetyl-4-amino-pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

By substituting 1-(4-amino-2-methanesulfinyl-pyrimidin-5-yl)-ethanone(Example 36) for 2-methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine inExample 13, 4.04 g (65%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 413; Found 413.

EXAMPLE 384-[4-(7-Amino-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

To a suspension of 0.58 g (14.6 mmol) of 60% sodium hydride in 10 mL oftetrahydrofuran, at 0° C. is added dropwise 2.58 g (14.56 mmol) ofdiethyl (cyanomethyl) phosphonate. The reaction mixture is stirred at 0°C. for 5 minutes, then at room temperature for 20 minutes. The mixtureis then cooled to 0° C. and treated with 2 g (4.85 mmol) of4-[4-(5-acetyl-4-amino-pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (Example 37). The mixture is stirred at roomtemperature overnight, and then treated with water and saturated aqueousammonium chloride. The resulting solid is collected by filtration andwashed with ether to give 1.069 g (80%) of the product.

MS (APCI) M+1: Calcd 436; Found 436.

EXAMPLE 394-{4-[7-(3-Cyclohexyl-ureido)-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting4-[4-(7-amino-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (Example 38) for4-[4-(7-amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester in Example 16, 0.199 g (420%) of the product as asolid is obtained.

MS (APCI) M+1: Calcd 561; Found 561.

EXAMPLE 401-Cyclohexyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting4-{4-[7-(3-cyclohexyl-ureido)-5-methyl-pyrido[2,3-d]pyrimidine-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Example 39) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15, the product (compound 12) as asolid is obtained, mp 238° C. (dec).

MS (APCI) M+1: Calcd 461; Found 461.

EXAMPLE 41 5-Methyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine

By substituting 1-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanone(Example 35) for4-[4-(5-acetyl-4-amino-pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester in Example 38, 0.97 g (85%) of the product as asolid is obtained.

MS (APCI) M+1: Calcd 207; Found 207.

EXAMPLE 42 2-Methanesulfinyl-5-methyl-pyrido[2,3-d]pyrimidin-7-ylamine

By substituting5-methyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine (Example 41)for 2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine in Example 8, 0.85g (83%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 223; Found 223.

EXAMPLE 434-[4-(7-Amino-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

By substituting2-methanesulfinyl-5-methyl-pyrido[2,3-d]pyrimidin-7-ylamine (Example 42)for 2-methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine in Example 13,0.33 g (20%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 436; Found 436.

EXAMPLE 444-{4-[7-(3-tert-Butyl-ureido)-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting4-[4-(7-amino-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (Example 43) forN²-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine in Example 10, 0.17 g(45%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 535; Found 535.

EXAMPLE 451-tert-Butyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting4-{4-[7-(3-tert-butyl-ureido)-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Example 44) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15, 0.070 g (72%) of the product(compound 4) as a solid is obtained, mp 230-232° C. (dec).

MS (APCI) M+1: Calcd 435; Found 435.

EXAMPLE 46 6-Fluoro-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

A solution of 1.74 g (10.33 mmol) of (diethoxy-phosphoryl)-fluoro-aceticacid ethyl ester in 20 mL of tetrahydrofuran is cooled to −78° C. andtreated dropwise with 12.9 mL (20.65 mmol) of a 1.6 M solution ofn-butyl lithium in hexanes. After stirring for 30 minutes at −78° C. thesolution is treated with 1.74 g (10.33 mmol) of4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3),allowed to warm to room temperature, and stirred overnight. The reactionis treated with saturated aqueous ammonium chloride, then water. Thesolid is collected by filtration and washed with diethyl ether to give2.01 g (92%) of the product.

MS (APCI) M+1: Calcd 212; Found 212.

EXAMPLE 47 7-Chloro-6-fluoro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine

By substituting6-fluoro-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (Example 46)for 2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one in Example 6 isobtained 1.86 g (85%) the product as a solid.

MS (APCI) M+1: Calcd 230, 232; Found 230, 232.

EXAMPLE 48 6-Fluoro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine-7-ylamine

By substituting7-chloro-6-fluoro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (Example 47)for 7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine in Example 7 isobtained 0.29 g (90%) of the product as a solid.

MS (APCI) M+1: Calcd 211; Found 211.

EXAMPLE 49 6-Fluoro-2-methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine

By substituting6-fluoro-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine (Example 48)for 2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine in Example 8, 0.26g (95%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 227; Found 227.

EXAMPLE 504-[4-(7-Amino-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting6-fluoro-2-methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine (Example 49)for 2-methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine in Example 27,0.040 g (63%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 468; Found 468.

EXAMPLE 514-{4-[7-(3-Cyclohexyl-ureido)-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting4-[4-(7-amino-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (Example 50) for4-[4-(7-amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester in Example 16, 0.10 g (74%) of the product as asolid is obtained.

MS (APCI) M+1: Calcd 593; Found 593.

EXAMPLE 521-Cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-urea

By substituting4-{4-[7-(3-cyclohexyl-ureido)-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (Example 51) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15, 0.060 g (75%) of the product(compound 52) as a solid is obtained, mp 227-229° C.

MS (APCI) M+1: Calcd 493; Found 493.

EXAMPLE 534-{4-[7-(3-Cyclopentyl-ureido)-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting4-[4-(7-amino-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (Example 43) for4-[4-(7-amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester in Example 32, 0.18 g (55%) of the product as asolid is obtained.

MS (APCI) M+1: Calcd 547; Found 547.

EXAMPLE 541-Cyclopentyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting4-{4-[7-(3-cyclopentyl-ureido)-5-methyl-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Example 53) for4-{4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester in Example 15, 0.08 g (70%) of the product(compound 53) is obtained, mp 234° C. (dec).

MS (APCI) M+1: Calcd 447; Found 447.

EXAMPLE 554(4-{7-[3-(3-Hydroxy-propyl)-ureido]-pyrido[2,3-d]pyrimidin-2-ylamino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

By substituting 3-amino-1-propanol for cyclopentylamine, and sodiumtertiary butoxide for sodium hydride in Example 32, 0.1295 g (52.2%) ofthe product as a solid is obtained.

MS (APCI) M+1: Calcd 523.3; Found 523.2.

EXAMPLE 561-(3-Hydroxy-propyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 55 in Example 15, 0.1077 g of theproduct (compound 81) as a solid is obtained, mp 183° C. (dec).

MS (APCI) M+1: Calcd 423; Found 423.1.

EXAMPLE 574-{4-[7-(3-Cyclohexyl-3-methyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting N-methylcyclohexylamine for 3-amino-1-propanol inExample 55, 0.1939 g (72.7%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 561.3; Found 561.2.

EXAMPLE 581-Cyclohexyl-1-methyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 57 in Example 15, 0.1645 g of theproduct (compound 65) as a solid is obtained, mp 177° C. (dec).

MS (APCI) M+1: Calcd 461.3; Found 461.2.

EXAMPLE 594-(4-{7-[3-((S)-1-Hydroxymethyl-3-methyl-butyl)-ureido]-pyrido[2,3-d]pyrimidin-2-ylamino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

By substituting (S)-(+)-leucinol for 3-amino-1-propanol in Example 55,0.1048 g (39.1%) of the product as a solid is obtained.

MS (APCI) M+1: Calcd 565.3; Found 565.3.

EXAMPLE 601-((S)-1-Hydroxymethyl-3-methyl-butyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 59 in Example 15, 0.0802 g of theproduct (compound 83) as a solid is obtained, mp 185° C. (dec).

MS (APCI) M+1: Calcd 465.3; Found 465.2.

EXAMPLE 614-[4-(7-{[1-(4-Methyl-piperazin-1-yl)-methanoyl]-amino}-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

By substituting N-methylpiperazine for 3-amino-1-propanol in Example 55,the product as a solid is obtained.

MS (APCI) M+1: Calcd 548.3; Found 548.3.

EXAMPLE 62 4-Methyl-piperazine-1-carboxylic acid[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-amide

By substituting the product of Example 61 in Example 15, 0.1194 g of theproduct (compound 84) as a solid is obtained, mp 200° C. (dec).

MS (APCI) M+1: Calcd 448.3; Found 448.2.

EXAMPLE 634-(4-{7-[(1-Morpholin-4-yl-methanoyl)-amino]-pyrido[2,3-d]pyrimidin-2-ylamino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

By substituting morpholine for 3-amino-1-propanol in Example 55, theproduct as a solid is obtained.

MS (APCI) M+1: Calcd 535.3; Found 535.2.

EXAMPLE 64 Morpholine-4-carboxylic acid[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-amide

By substituting the product of Example 63 in Example 15, 0.1132 g of theproduct (compound 85) as a solid is obtained, mp 190° C. (dec).

MS (APCI) M+1: Calcd 435.2; Found 435.2.

EXAMPLE 654-{4-[7-(3,3-Dipropyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting dipropylamine for 3-amino-1-propanol in Example 55, theproduct as a solid is obtained.

MS (APCI) M+1: Calcd 549.3; Found 549.3.

EXAMPLE 663-[2-(4-Piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-1,1-dipropylurea

By substituting the product of Example 65 in Example 15, 0.1278 g of theproduct (compound 86) as a solid is obtained, mp 190° C. (dec).

MS (APCI) M+1: Calcd 449.3; Found 449.2.

EXAMPLE 674-[4-(7-{[1-(4-Boc-piperazin-1-yl)-methanoyl]-amino}-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

By substituting Boc-piperazine for 3-amino-1-propanol in Example 55, theproduct as a solid is obtained.

MS (APCI) M+1: Calcd 634.3; Found 634.3.

EXAMPLE 68 Piperazine-1-carboxylic acid[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-amide

By substituting the product of Example 67 in Example 15, 0.0342 g of theproduct (compound 87) as a solid is obtained, mp 220° C. (dec).

MS (APCI) M+1: Calcd 434.2; Found 434.2.

EXAMPLE 694-(4-{7-[3-((R)-1-Hydroxymethyl-2-methyl-propyl)-ureido]-pyrido[2,3-d]pyrimidin-2-ylamino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

By substituting (R)-valinol for 3-amino-1-propanol in Example 55, theproduct as a solid is obtained.

MS (APCI) M+1: Calcd 551.3; Found 551.3.

EXAMPLE 701-((R)-1-Hydroxymethyl-2-methyl-propyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 69 in Example 15, 0.0639 g of theproduct (compound 88) as a solid is obtained, mp 200° C. (dec).

MS (APCI) M+1: Calcd 451.3; Found 451.2.

EXAMPLE 714-(4-{7-[3,3-Bis-(2-Hydroxy-ethyl)-ureido]-pyrido[2,3-d]pyrimidin-2-ylamino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

By substituting diethanolamine for 3-amino-1-propanol in Example 55, theproduct as a solid is obtained.

MS (APCI) M+1: Calcd 553.3; Found 553.2.

EXAMPLE 721,1-Bis-(2-hydroxy-ethyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 71 in Example 15, 0.0916 g of theproduct (compound 89) as a solid is obtained, mp 185° C. (dec).

MS (APCI) M+1: Calcd 453.2; Found 453.2.

EXAMPLE 73 6-Bromo-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

To 5.00 g (25.9 mmol) of2-methanesulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (Example 5) in 130 mLof DMF is added 5.00 g (28.1 mmol) of N-bromosuccinimide. The resultingsuspension is stirred at room temperature overnight and concentrated.The solid is triturated with hot water, then washed with isopropanol togive 5.59 g (79.4%) of the product as a solid, mp 266-270° C.

EXAMPLE 74 6-Bromo-7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine

By substituting the product of Example 73 in Example 6, 2.73 g (97.2%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 289.9; Found 289.8.

EXAMPLE 75 6-Bromo-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine

By substituting the product of Example 74 in Example 7, 2.09 g (82.9%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 271.0; Found 270.8.

EXAMPLE 76 6-Bromo-2-methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine

By substituting the product of Example 75 in Example 8, 1.81 g (81.9%)of the product is obtained as a solid, mp 245° C. (dec).

MS (APCI) M+1: Calcd 287.0; Found 286.8.

EXAMPLE 774-[4-7-Amino-6-bromo-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 76 in Example 13, 1.40 g (44.4%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 500.1; Found 500.0.

EXAMPLE 784-{4-[6-Bromo-7-(3-cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 77 in Example 16, 0.1160 g(46.4%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 625.2; Found 625.1.

EXAMPLE 791-[6-Bromo-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-cyclohexyl-urea

By substituting the product of Example 78 in Example 15, 0.0886 g(77.0%) of the product (compound 55) is obtained as a solid, mp 195° C.(dec).

MS (APCI) M+1: Calcd 525.2; Found 525.1.

Anal. Calcd for C₂₄H₂₉Br₁N₈O₁.1.64 H₂O.1.83 HCl: C, 46.37; H, 5.53; N,18.02; Cl, 10.44. Found: C, 46.53; H, 5.34; N, 17.73; Cl, 10.15.

EXAMPLE 804-{4-[6-Bromo-7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 77 in Example 10, 0.2571 g(42.9%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 599.2; Found 599.2.

EXAMPLE 811-[6-Bromo-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-tert-butyl-urea

By substituting the product of Example 80 in Example 15, 0.0481 g of theproduct (compound 91) is obtained as a solid.

MS (APCI) M+1: Calcd 499.2; Found 499.0.

EXAMPLE 824-{4-[6-Bromo-7-(3-methyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 77 and methylamine in Example 32,0.170 g (29.9%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 557.2; Found 557.1.

EXAMPLE 831-[6-Bromo-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-methyl-urea

By substituting the product of Example 82 in Example 15, 0.0963 g (69%)of the product (compound 93) is obtained as a solid.

MS (APCI) M+1: Calcd 457.1; Found 457.1.

Anal. Calcd for C₁₉H₂₁Br₁N₈O₁.3 HCl.3 H₂O: C, 36.76; H, 4.87; N, 18.05;Cl, 17.13; H₂O, 8.71. Found: C, 36.49; H, 4.35; N, 17.52; Cl, 15.79;H₂O, 8.12.

EXAMPLE 844-[4-(7-Amino-6-bromo-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 76 in Example 27, 2.10 g (63.1%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 528.2; Found 528.2.

EXAMPLE 854-{4-[6-Bromo-7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 84 in Example 10, 0.1725 (72.6%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 627.2; Found 627.2.

EXAMPLE 861-{6-Bromo-2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea

By substituting the product of Example 85 in Example 15, 0.1593 g(96.0%) of the product (compound 94) is obtained as a solid, mp 20° C.(dec).

MS (APCI) M+1: Calcd 527.2; Found 527.2.

Anal. Calcd for C₂₄H₃₁Br₁N₈O₁.2.55 HCl.1.70 H₂O: C, 44.28; H, 5.72; N,17.21; Cl, 13.89. Found: C, 44.28; H, 5.72; N, 17.09; Cl, 12.49.

EXAMPLE 874-{4-[6-Bromo-7-(3-cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 84 in Example 16, 0.1750 g(70.7%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 653.3; Found 653.3.

EXAMPLE 881-{6-Bromo-2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea

By substituting the product of Example 87 in Example 15, 0.1614 g(95.4%) of the product (compound 95) is obtained as a solid, mp 198° C.(dec).

MS (APCI) M+1: Calcd 553.2; Found 553.2.

Anal. Calcd for C₂₆H₃₃N₈O₁Br₁.2.76 HCl.2.02 H₂O: C, 45.22; H, 5.81; N,16.23; Cl, 14.17. Found: C, 45.23; H, 5.82; N, 16.08; Cl, 13.53.

EXAMPLE 89 N²-(4-Fluoro-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine

By substituting 4-fluoroaniline in Example 9, 1.1529 g (45.2%) of theproduct is obtained as a solid, mp 245-248° C.

MS (APCI) M+1: Calcd 256.1; Found 255.9.

EXAMPLE 901-[2-(4-Fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(3-morpholin-4-yl-propyl)-urea

By substituting the product of Example 89 and3-morpholin-4-yl-propylamine in Example 32, 0.1465 g (58.6%) of theproduct (compound 96) is obtained as a solid, mp 253-256° C.

MS (APCI) M+1: Calcd 426.2; Found 426.1.

Anal. Calcd for C₂₁H₂₄F₁N₇O₂: C, 59.28; H, 5.69; N, 23.04. Found: C,59.18; H, 5.66; N, 23.04.

EXAMPLE 911-[2-(4-Fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(2-hydroxy-ethyl)-urea

By substituting the product of Example 89 and 2-hydroxy-ethylamine inExample 32, 0.0811 g (40.3%) of the product (compound 97) is obtained asa solid, mp 238-240° C.

MS (APCI) M+1: Calcd 343.1; Found 343.1.

Anal. Calcd for C₁₆H₁₅F₁N₆O₂: C, 56.14; H, 4.42; N, 24.55. Found: C,55.82; H, 4.52; N, 24.15.

EXAMPLE 921-(2-Amino-ethyl)-3-[2-(4-fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 89 and ethylenediamine in Example32, 0.1000 g (49.3%) of the product (compound 98) is obtained as asolid, mp 217-220° C.

MS (APCI) M+1: Calcd 342.1; Found 342.0.

Anal. Calcd for C₁₆H₁₆F₁N₇O₁.0.2 H₂O: C, 55.71; H, 4.79; N, 28.42.Found: C, 55.72; H, 4.57; N, 28.07.

EXAMPLE 931-(2-Dimethylamino-ethyl)-3-[2-(4-fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 89 and 2-dimethylamino-ethylaminein Example 32, 0.0778 g (35.8%) of the product (compound 99) is obtainedas a solid, mp 251-255° C.

MS (APCI) M+1: Calcd 370.2; Found 370.0.

Anal. Calcd for C₁₈H₂₀F₁N₇O₁: C, 58.53; Hz 5.46; N, 26.54. Found: C,58.39; H, 5.51; N, 26.26.

EXAMPLE 94 3,3-Dimethyl-1-(4-nitro-phenyl)-piperazine

By substituting 2,2-dimethyl-piperazine in Example 24, 29.43 g (88.4%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 236; Found 236.

EXAMPLE 95 2-2-Dimethyl-4-(4-nitro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

By substituting the product of Example 94 in Example 11, 38 g (93%) ofthe product is obtained as a solid.

MS (APCI) M+1: Calcd 336; Found 336.

EXAMPLE 96 4-(4-Amino-phenyl)-2,2-dimethyl-piperazine-1-carboxylic acidtert-butyl ester

By substituting the product of Example 95 in Example 12, 27 g (78%) ofthe product is obtained as a solid.

MS (APCI) M+1: Calcd 306; Found 306.

EXAMPLE 974-[4-(7-Amino-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-2,2-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 96 in Example 50, 0.4346 g(59.0%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 468.2; Found 468.3.

EXAMPLE 984-{4-[7-(3-Cyclohexyl-ureido)-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-2,2-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 97 in Example 16, 0.170 g (31.2%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 593.2; Found 593.4.

EXAMPLE 991-Cyclohexyl-3-{2-[4-(3,3-dimethyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-urea

By substituting the product of Example 98 in Example 15, 0.040 g of theproduct (compound 100) is obtained as a solid.

MS (APCI) M+1: Calcd 493.3; Found 493.2.

EXAMPLE 1004-[4-(7-Amino-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 12 in Example 50, 0.2017 g(29.7%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 440.2; Found 440.2.

EXAMPLE 1014-{4-[7-(3-Cyclohexyl-ureido)-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 100 in Example 16, 0.2036 g(78.6%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 565.3; Found 565.3.

EXAMPLE 1021-Cyclohexyl-3-[6-fluoro-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 101 in Example 15, 0.1084 g(96.0%) of the product (compound 11) is obtained as a solid.

MS (APCI) M+1: Calcd 465.2; Found 465.2.

Anal. Calcd for C₂₄H₂₉F₁N₈O₁.2.75 HCl.3.5 H₂O: C, 45.91; H, 5.10; N,17.85; Cl, 15.53; H₂O, 10.04. Found: C, 46.20; H, 5.86; N, 17.45; Cl,15.22; H₂O, 8.97.

EXAMPLE 1034-{4-[7-(3-tert-Butyl-ureido)-6-fluoro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester

By substituting the product of Example 50 in Example 10, 0.070 g (17.9%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 567.3; Found 567.3.

EXAMPLE 1041-tert-Butyl-3-{2-[4(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-urea

By substituting the product of Example 103 in Example 15, 0.0585 g ofthe product (compound 102) is obtained as a solid.

MS (APCI) M+1: Calcd 467.3; Found 467.3.

EXAMPLE 105 1-[4-(4-Nitro-phenyl)-piperazinyl]-ethanone

To a solution of 5.0 g (24.1 mmol) of 1-(4-nitro-phenyl)-piperazine in100 mL of dichloromethane was added 5.04 mL (28.9 mmol) ofdiisopropyl-ethylamine. The solution is cooled in an ice-bath, treatedwith 1.89 mL (26.5 mmol) of acetyl chloride, and stirred at roomtemperature overnight. The reaction is washed successively with water,0.5 M HCl, saturated sodium hydrogen carbonate, and brine, and driedover magnesium sulfate, and concentrated to give 5.91 g (98.5%) of theproduct as a solid.

MS (APCI) M+1: Calcd 250.1; Found 250.0.

EXAMPLE 106 1-[4-(4-Amino-phenyl)-piperazin-1-yl]-ethanone

By substituting the product of Example 105 in Example 12, 4.35 g (84.1%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 220.1; Found 220.1.

EXAMPLE 1071-{4-[4-(7-Amino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazin-1-yl}-ethanone

By substituting the product of Example 106 in Example 9, 0.1829 g(50.1%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 364.2; Found 364.2.

Anal. Calcd for C₁₉H₂₁N₇O₁.1.0 H₂O: C, 59.46; H, 6.11; N, 25.55. Found:C, 59.51; H, 6.03; N, 25.28.

EXAMPLE 1081-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(3-morpholin-4-yl-propyl)-urea

By substituting the product of Example 107 and3-morpholin-4-yl-propylamine in Example 32, 0.0338 g (22.6%) of theproduct (compound 103) is obtained as a solid, mp 221-225° C. (dec).

MS (APCI) M+1: Calcd 534.3; Found 534.2.

Anal. Calcd for C₂₇H₃₅N₉O₃.0.5 H₂O: C, 59.76; H, 6.69; N, 23.25. Found:C, 59.74; H, 6.53; N, 23.35.

EXAMPLE 109 6-Chloro-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

By substituting N-chlorosuccinimide in Example 74, 0.3700 g (31.4%) ofthe product is obtained as a solid, mp 264-266° C. (dec).

MS (APCI) M+1: Calcd 228.0; Found 227.9.

EXAMPLE 110 6,7-Dichloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine

By substituting the product of Example 109 in Example 6, 0.6534 g(86.5%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 246.0; Found 245.8.

EXAMPLE 111 6-Chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine

By substituting the product of Example 110 in Example 7, 0.38 g (63%) ofthe product is obtained as a solid.

MS (APCI) M+1: Calcd 227.0; Found 226.9.

EXAMPLE 112 6-Chloro-2-methanesulfinyl-pyrido[2,3-d]pyrimidin-7-ylamine

By substituting the product of Example 111 in Example 8, 0.2328 g(57.1%) of the product is obtained as a solid, mp 260-262° C.

MS (APCI) M+1: Calcd 243.0; Found 242.9.

EXAMPLE 1134-[4-(7-Amino-6-chloro-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 112 in Example 27, 0.22 g (49%)of the product is obtained as a solid.

MS (APCI) M+1: Calcd 484.2; Found 484.2.

EXAMPLE 1144-{4-[7-(3-tert-Butyl-ureido)-6-chloro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-cis-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 113 in Example 10, 0.0995 g(39.2%) of the product is obtained as a solid.

EXAMPLE 1151-tert-Butyl-3-{6-chloro-2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea

By substituting the product of Example 114 in Example 15, 0.0995 g ofthe product (compound 104) is obtained as a solid, mp 205° C. (dec).

MS (APCI) M+1: Calcd 483.2; Found 483.2.

EXAMPLE 116 Methyl-(2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-yl)-amine

By substituting methylamine in Example 7, 1.46 g (30.0%) of the productis obtained as a solid.

MS (APCI) M+1: Calcd 207.1; Found 206.9.

EXAMPLE 117 (2-Methanesulfinyl-pyrido[2,3-d]pyrimidin-7-yl)-methyl-amine

By substituting the product of Example 116 in Example 8, 1.31 g (83.4%)of the product is obtained as a solid, mp 185° C.

MS (APCI) M+1: Calcd 223.1; Found 223.0.

EXAMPLE 1184-[4-(7-Methylamino-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 117 in Example 13, 0.4934 g(62.9%) of the product is obtained as a solid.

MS (APCI) M+1: Calcd 436.2; Found 436.2.

EXAMPLE 1194-{4-[7-(3-Cyclohexyl-1-methyl-ureido)-pyrido[2,3-d]pyrimidin-2-yl]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

By substituting the product of Example 118 in Example 16, and usingacetonitrile as solvent and no base, 0.8535 g (78.8%) of the product isobtained as a solid.

MS (APCI) M+1: Calcd 561.3; Found 561.3.

EXAMPLE 1203-Cyclohexyl-1-methyl-1-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

By substituting the product of Example 119 in Example 15, 0.2548 g(36.0%) of the product (compound 70) is obtained as a solid, mp 169-175°C.

MS (APCI) M+1: Calcd 461.3; Found 461.2.

Anal. Calcd for C₂₅H₃₂N₈O₁.0.25 H₂O: C, 64.56; H, 7.04; N, 24.09. Found:C, 64.57; H, 7.01; N, 23.98.

EXAMPLE 1213-Cyclohexyl-1-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-}-1-methyl-urea

Using the general procedure by which Example 120 is synthesized, 0.1366g (95.6%) of the product (compound 106) is obtained as a solid, mp 170°C. (dec).

MS (APCI) M+1: Calcd 489.3; Found 489.3.

Anal. Calcd for C₂₇H₃₆N₈O₁.3.32 H₂O.2.69 HCl: C, 50.16; H, 7.07; N,17.33; Cl, 14.75. Found: C, 50.36; H, 6.98; N, 16.97; Cl, 15.07.

EXAMPLE 1223-Cyclohexyl-1-ethyl-1-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

Using the general procedure by which Example 120 is synthesized, 0.118 g(94%) of the product (compound 107) is obtained as a solid.

MS (APCI) M+1: Calcd 475.3; Found 475.3.

Anal. Calcd for C₂₆H₃₄N₈O₁.3.0 HCl.0.3 diethylether: C, 53.89; H, 6.65;N, 18.48. Found: C, 53.75; H, 6.96; N, 18.57.

EXAMPLE 1233-tert-Butyl-1-{2-[4(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-1-ethyl-urea

Using the general procedure by which Example 15 is synthesized, 0.022 g(56%) of the product (compound 108) is obtained as a solid.

MS (APCI) M+1: Calcd 477.3; Found 477.3.

EXAMPLE 1241-Methyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

Using the general procedure by which Example 40 is synthesized, theproduct (compound 64) is obtained as a solid, mp 204-206° C. (dec).

MS (APCI) M+1: Calcd 393; Found 393.

EXAMPLE 1251-Ethyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

Using the general procedure by which Example 40 is synthesized theproduct (compound 28) is obtained as a solid, mp 220-222° C.

MS (APCI) M+1: Calcd 407; Found 407.

EXAMPLE 1261-[5-Methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-propyl-urea

Using the general procedure by which Example 40 is synthesized, theproduct (compound 111) is obtained as a solid, mp 223-225° C.

MS (APCI) M+1: Calcd 421; Found 421.

EXAMPLE 127N,N-Dimethyl-N′-[5-methyl-2-[[4-(1-piperazinyl)phenyl]-amino]-pyrido[2,3-d]pyrimidin-7-yl-sulfamide

Using the general procedure by which Example 40 is synthesized, butusing dimethyl sulfamyl chloride rather than cyclohexylisocyanate, theproduct (compound 71) is obtained as a solid, mp 228-230° C. (dec).

MS (APCI) M+1: Calcd 443; Found 443.

EXAMPLE 1287-Amino-2-methylsulfanyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylester

To a solution of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde(Example 3) in 10 mL of tetrahydrofuran is added 0.126 mL (1.18 mmol) ofethyl cyanoacetate. The solution is cooled to −10° C., and treated with2.36 mL (2.36 mmol) of titanium tetrachloride. To the solution is slowlyadded 0.52 mL (4.72 mmol) of N-methyl morpholine. The reaction is warmedto room temperature over 2 hours, and partitioned between ethyl acetateand saturated aqueous ammonium chloride. The organic layer isconcentrated to give a solid, which is triturated with ether to give0.30 g (96%) of the product as a solid.

MS (APCI) M+1: Calcd 265.1; Found 264.9.

EXAMPLE 129 7-Amino-2-chloro-pyrido[2,3-d]pyrimidine-6-carboxylic acidethyl ester

To a suspension of the product of Example 128 in 50 mL of chloroform isslowly added sulfuryl chloride, followed by 2 drops of ethanol. Thereaction is stirred at room temperature for 16 hours, poured into ether,and the solid collected to give 0.50 g (98%) of the product.

MS (APCI) M+1: Calcd 253.1; Found 253.1.

EXAMPLE 1307-Amino-2-[4-(4-tert-butoxycarbonyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester

A solution of the product of Example 12 and the product of Example 129in dioxane is heated under reflux for 1.5 hours. The reaction is pouredinto hexane/ethyl acetate (1:1), and the solid is collected. Flashchromatography using dichloromethane as eluant gave 0.08 g (16%) of theproduct as a solid.

MS (APCI) M+1: Calcd 494.2; Found 494.1.

EXAMPLE 1312-[4-(4-tert-Butoxycarbonyl-piperazin-1-yl)-phenylamino]-7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester

By substituting the product of Example 130 in Example 10, 0.05 g (48%)of the product as a solid is obtained.

EXAMPLE 1327-(3-tert-Butyl-ureido)-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester

By substituting the product of Example 131 in Example 15, 0.036 g of theproduct (compound 113) as a solid is obtained, mp>300° C.

EXAMPLE 1331-[6-Fluoro-5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-isopropyl-urea

Using the general procedure by which Example 52 is synthesized, butusing 1-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanone (Example 35),4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester(Example 12), and isopropyl isocyanate as reagents, the product(compound 114) is obtained as a solid, mp 208° C. (dec).

MS (APCI) M+1: Calcd 439.2; Found 439.3.

EXAMPLE 1341-Cyclohexyl-3-{2-[4-(3,3-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea

Using the general procedure by which Example 17 is synthesized, butusing 4-(4-amino-phenyl)-2,2-dimethyl-piperazine-1-carboxylic acidtert-butyl ester (Example 96), 0.95 g (100%) of the product (compound115) is obtained as a solid.

MS (APCI) M+1: Calcd 475.6; Found 475.3.

Anal. Calcd for C₂₆H₃₄N₈O₁.3 HCl.1 H₂O: C, 51.96; H, 6.37; N, 18.64; Cl,17.69; H₂O, 2.99. Found: C, 52.00; H, 6.41; N, 18.53; Cl, 16.51; H₂O,3.06.

EXAMPLE 135 6-Methyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine

To a suspension of 2.18 g (54 mmol) of 60% oil dispersed sodium hydridein 300 mL of tetrahydrofuran, cooled to 10° C. is added 10.2 g (53.4mmol) of (1-cyano-1-methyl-methyl)-phosphonic acid diethyl ester(Synthesis, 1975:516). To the cooled suspension is added 4.30 g (25.4mmol) of 4-amino-2-methanesulfanyl-pyrimidine-5-carboxaldehyde (Example3), and the reaction is stirred at room temperature for 22 hours. Theresulting solution is concentrated and filtered to give a solid, whichis washed with tetrahydrofuran, dissolved in 1N citric acid, andre-precipitated by adjusting the pH to 8 with 50% sodium hydroxide. Thesolid is collected by filtration to give 1.1 g (21%) of the product, mp268-270° C.

MS (APCI) M+1: Calcd 207.3; Found 207.0.

EXAMPLE 1361-Cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-methyl-pyrido[2,3-d]pyrimidin-7-yl}-urea

Using the general procedure by which Example 31 is synthesized, butusing the product of Example 135 as the starting material, 0.14 g (420%)of the product (compound 116) is obtained as a solid.

MS (APCI) M+1: Calcd 589.6; Found 589.3.

Anal. Calcd for C₂₇H₃₆N₈O₁.2.5 HCl.1.5 H₂O: C, 53.80; H, 6.73; N, 18.01;Cl, 14.11; H₂O, 4.06. Found: C, 53.44; H, 6.89; N, 18.46; Cl, 14.60;H₂O, 4.48.

EXAMPLE 1371-tert-Butyl-3-{2-[4(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-methyl-pyrido[2,3-d]pyrimidin-7-yl}-urea

Using the general procedure by which Example 29 is synthesized, butusing the product of Example 135 as the starting material, 0.26 g (89%)of the product (compound 117) is obtained as a solid.

MS (APCI) M+1: Calcd 463.6; Found 463.3.

Anal. Calcd for C₂₅H₃₆N₈O₁.2.4 HCl.1.75 H₂O: C, 51.62; H, 6.91; N,19.26; Cl, 14.63; H₂O, 5.42. Found: C, 51.23; H, 6.55; N, 18.92; Cl,14.73; H₂O, 5.10.

EXAMPLE 1381-tert-Butyl-3-[6-methyl-2-(4-piperazin-1-yl)-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea

Using the general procedure by which Example 15 is synthesized, butusing the product of Example 135 as the starting material, 1.02 g (100%)of the product (compound 118) is obtained as a solid.

MS (APCI) M+1: Calcd 435.3; Found 435.3.

Anal. Calcd for C₂₃H₃₀N₈O₁.5 HCl.1.75 H₂O: C, 42.60; H, 5.98; N, 17.28;Cl, 27.34; H₂O, 4.86. Found: C, 42.03; H, 6.04; N, 16.81; Cl, 22.95;H₂O, 4.72.

EXAMPLE 1391-{2-[4-(cis-3,5-Dimethyl-piperazin-1-yl)-phenylamino]-6-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-isopropyl-urea

Using the general procedure by which Example 33 is synthesized, butusing the product of Example 135 as the starting material, along with4-(4-amino-phenyl)-cis-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester and isopropylamine as reagents, 0.130 g (100%) of theproduct (compound 119) is obtained as a solid.

MS (APCI) M+1: Calcd 449.3; Found 449.3.

Anal. Calcd for C₂₄H₃₂N₈O₁.3 HCl.1.75 H₂O: C, 48.90; H, 6.58; N, 19.01;Cl, 16.04; H₂O, 5.35. Found: C, 49.03; H, 6.63; N, 18.70; Cl, 16.03;H₂O, 5.19.

EXAMPLE 1401-Cyclopropyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-methyl-pyrido[2,3-d]pyrimidin-7-yl}-urea

Using the general procedure by which Example 33 is synthesized, butusing the product of Example 135 as the starting material, along with4-(4-amino-phenyl)-cis-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester and cyclopropylamine as reagents, 0.099 g (100%) of theproduct (compound 120) is obtained as a solid.

MS (APCI) M+1: Calcd 447.3; Found 447.3.

Anal. Calcd for C₂₄H₃₀N₈O₁: C, 49.83; H, 6.19; N, 19.37; Cl, 18.39; H₂O,3.89. Found: C, 49.76; H, 6.23; N, 18.92; Cl, 15.66; H₂O, 3.06.

EXAMPLE 1411-tert-Butyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-ethyl-pyrido[2,3-d]pyrimidin-7-yl}-urea

Using the general procedure by which Example 137 is synthesized, butusing (1-cyano-propyl)-phosphonic acid diethyl ester as startingmaterial, 0.34 g (95%) of the product (compound 121) is obtained as asolid.

MS (APCI) M+1: Calcd 477.3; Found 477.3.

Anal. Calcd for C₂₆H₂₆N₈O₁.2.5 HCl.1 H₂O: C, 53.26; H, 7.05; N, 19.11;Cl, 15.18; H₂O, 3.07. Found: C, 53.63; H, 7.31; N, 18.46; Cl, 15.32;H₂O, 3.48.

EXAMPLE 142

The following compounds are prepared essentially according to theprocedures described in Examples 1-141 and shown in Schemes 1-4:

(a)1-tert-Butyl-3-[2-(3-chloro-4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 2);

(b)1-tert-Butyl-3-[6-fluoro-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 3);

(c)1-{2-[4-(4-Acetyl-piperazin-1-yl)-3-chloro-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea(compound 6);

(d)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea(compound 7);

(e)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea(compound 8);

(f)1-[2-(3-Chloro-4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-cyclohexyl-urea(compound 10);

(g)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea(compound 13);

(h)1-{2-[4-(4-Acetyl-piperazin-1-yl)-3-chloro-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea(compound 14);

(i)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea(compound 15);

(j)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea(compound 16);

(k)1-(2-Hydroxy-ethyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 17);

(l)1-[2-(3-Chloro-4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(2-hydroxy-ethyl)-urea(compound 18);

(m)1-[6-Fluoro-2-(4-piperazin-1-yl)-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(2-hydroxy-ethyl)-urea(compound 19);

(n)1-(2-Hydroxy-ethyl)-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 20);

(o)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-hydroxy-ethyl)-urea(compound 21);

(p)1-{2-[4-(4-Acetyl-piperazin-1-yl)-3-chloro-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-hydroxy-ethyl)-urea(compound 22);

(q)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-hydroxy-ethyl)-urea(compound 23);

(r)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-hydroxy-ethyl)-urea(compound 24);

(s)1-Ethyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 25);

(t)1-[2-(3-Chloro-4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-ethyl-urea(compound 26);

(u)1-Ethyl-3-[6-fluoro-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 27);

(v)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-ethyl-urea(compound 29);

(w)1-{2-[4-(4-Acetyl-piperazin-1-yl)-3-chloro-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-ethyl-urea(compound 30);

(x)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-3-ethyl-urea(compound 31);

(y)1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-ethyl-urea(compound 32);

(z)1-tert-Butyl-3-[2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 33);

(aa)1-Cyclohexyl-3-[2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 34);

(bb) 1-Ethyl-3-[2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 35);

(cc)1-(Hydroxy-ethyl)-3-[2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 36);

(dd)1-tert-Butyl-3-[6-fluoro-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 37);

(ee)1-Cyclohexyl-3-[6-fluoro-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 38);

(ff)1-Ethyl-3-[6-fluoro-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 39);

(gg)1-[6-Fluoro-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(2-hydroxy-ethyl)-urea(compound 40);

(hh)1-tert-Butyl-3-[5-methyl-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 41);

(ii)1-Cyclohexyl-3-[5-methyl-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 42);

(jj)1-Ethyl-3-[5-methyl-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 43);

(kk)1-(2-Hydroxy-ethyl)-3-[5-methyl-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 44);

(ll)1-Cyclohexyl-3-[6-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 54);

(mm)1-Cyclohexyl-3-[6-cyano-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 56);

(nn)1-Cyclohexyl-3-[6-chloro-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 57);

(oo)1-Cyclohexyl-3-[6-fluoro-5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 58);

(pp)1-Cyclohexyl-3-[6-bromo-5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 59);

(qq)1-Cyclohexyl-3-[6-chloro-5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 60);

(rr)1-Isopropyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 61);

(ss)1-[5-Methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 63);

(tt)1-(4-Hydroxy-cyclohexyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 66);

(uu)1-(4-Amino-cyclohexyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 67);

(vv)1-(2-Dimethylamino-ethyl)-3-[-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 68);

(ww)1-(3-Morpholino-4-yl-propyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 69);

(xx)1-Cyclohexyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-thiourea(compound 72);

(yy)N-[2-(4-Piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-acetamide(compound 73);

(zz)4-[7-(3-Cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-benzenesulfonamide(compound 74);

(aaa)1-Cyclohexyl-3-{2-[4-(1-piperazin-1-yl-methanoyl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea(compound 75);

(bbb)1-Cyclohexyl-3-[2-(4-fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea(compound 76);

(ccc)1-(2-{4-[4-(2-Amino-4-methyl-pentanoyl)-piperazin-1-yl]-phenylamino}-pyrido[2,3-d]pyrimidin-7-yl)-3-cyclohexyl-urea(compound 77); and

(ddd)1-(2-{4-[4-(2-Amino-3-methyl-butanoyl)-piperazin-1-yl]-phenylamino}-pyrido[2,3-d]pyrimidin-7-yl)-3-cyclohexyl-urea(compound 78).

EXAMPLE 143

Biological Assay

As noted above, the compounds of this invention are potent inhibitors ofcdks, and accordingly, are useful in treating and preventingatherosclerosis and other cell proliferative disorders like cancer thatare mediated by such cdk enzymes. The compounds exhibit excellentinhibitor activity against a number of cdk enzymes, includingcdkcdk1/cyclinB, cdk2/cyclinA, cdk2/cyclinE, and cdk4/cyclinD, whenevaluated in standard assays routinely utilized by those skilled in theart to measure cdk inhibitors activities. Typical assays are carried outas follows.

Cyclin Dependent Kinase 4 (cdk-4) Assay

Enzyme assays for IC₅₀ determinations and kinetic evaluation areperformed in 96-well filter plates (Millipore MADVN6550). The totalvolume is 0.1 mL containing a final concentration of 20 mM TRIS(tris[hydroxymethyl]aminomethane), at pH 7.4, 50 mM NaCl, 1 mMdithiothreitol, 10 mM MgCl₂, 25 μM ATP containing 0.25 μCi of [³²P]ATP,20 ng of cdk4, 1 μg of retinoblastoma, and appropriate dilutions of acompound of the present invention. All components except the ATP areadded to the wells, and the plate is placed on a plate mixer for 2minutes. The reaction is started by adding [³²P]ATP, and the plate isincubated at 25° C. for 15 minutes. The reaction is terminated byaddition of 0.1 mL of 20% trichloroacetic acid (TCA). The plate is keptat 4° C. for at least 1 hour to allow the substrate to precipitate. Thewells are then washed 5 times with 0.2 mL of 10% TCA and ³²Pincorporation is determined with a beta plate counter (Wallac Inc.,Gaithersburg, Md.).

Cyclin Dependent Kinase 1 and 2 Assays (cdk1/cyclinB, cdk2/cyclinA,cdk2/cyclinE)

Enzyme assays for IC₅₀ determinations and kinetic evaluation areperformed in a 96-well filter plate (Millipore MADVN6550) in a totalvolume of 0.1 mL of 20 mM TRIS (tris[hydroxymethyl]aminomethane), at pH7.4, 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl₂, 12 mM ATP containing0.25 μCi of [³²P]ATP, 20 ng of enzyme (either cdk1/B, cdk2/A, or cdk2E),1 μg retinoblastoma and appropriate dilutions of the particularinvention compound. All components except the ATP are added to thewells, and the plate is placed on a plate mixer for 2 minutes. Thereaction is begun by addition of [³²P]ATP, and the plate is incubated at25° C. for 15 minutes. The reaction is terminated by addition of 0.1 mLof 20% TCA. The plate is kept at 4° C. for at least 1 hour to allow thesubstrate to precipitate. The wells are then washed 5 times with 0.2 mLof 10% TCA and ³²P incorporation determined with a beta plate counter(Wallac Inc., Gaithersburg, Md.).

Cyclin Dependent Kinase 5/p25 Proline-directed Protein Kinase Assay

Source of enzyme: recombinant baculovirus-infected insect cellsf9-expressed recombinant cdk5-p25 complex.

Purpose: To evaluate the ability of test agents to inhibit cdk5/p25phosphorylation of Histone H1.

Method: Baculovirus-insect cell His-tagged cdk5/Glu-tagged p25 (orGST-p25) enzyme complex is diluted to a concentration of 50 ng/20 μL inEnzyme Dilution Buffer (EDB—50 mM Tris-HCl [pH 8.0], 10 mM NaCl, 10 mMMgCl₂, and 1 mM DTT). A 20 μL sample of test agent (diluted in EDB) isthen combined with 20 μL of the of the final cdk5/p25 enzyme preparationand allowed to stand for 5 minutes at room temperature. Twenty-fivemicroliters of substrate solution containing 115 μL/mL Histone H1, 30 μMATP (vanadate-free), and 30 μCi/mL γ-³³P ATP (Amersham) in EDB is thenadded to the test agent/enzyme preparation and shaken at 30° C. for 45minutes. A 50 μL sample of the final preparation is added to 100 mL of150 mM phosphoric acid on ice for 30 minutes to facilitateprecipitation. The precipitate is then filtered through a 96-wellphosphocellulose filter plate and subsequently rinsed 3 times with 75 mMphosphoric acid. Each well then receives 20 μL of scintillationcocktail, and the plates are counted for beta emissions using a TriluxCounter (³³P filter protocol). Test samples are compared to Control (notest agent present: as 0% inhibition) and Baseline level (no enzyme, notest agent: as 100% inhibition) beta emissions to determine the percentinhibition of Histone H1 phosphorylation.

The results of the foregoing assays for representative inventioncompounds are presented in Table 2 below. The invention compoundsexhibit IC₅₀ values ranging from 0.027 μM to >5 μM against cdk1/B, from0.010 μM to >5 μM against cdk2/A, from 0.020 to >5 μM against cdk2/E,and from 0.004 to >5 μM against cdk4/D. The most potent compound overallis compound 9, which exhibits IC₅₀ values of 0.027 μM, 0.010 μM, 0.020μM 0.005 μM, against cdk1/B, cdk2A, cdk2E, and cdk4D, respectively.

TABLE 2 Inhibition of Cdks: IC₅₀ (μM) Compound Cdk1/B Cdk2/A Cdk2/ECdk4D 1 0.219 0.060 0.130 0.006 4 >5 >5 >5 1.5 5 0.463 0.130 0.130 0.0379 0.027 0.010 0.020 0.005 11 0.159 0.092 0.125 0.011 12 >5 >5 >5 2.10028 >5 >5 >5 >5 45 0.552 0.054 0.110 0.045 46 0.075 0.300 >547 >5 >5 >5 >5 48 0.257 0.113 0.098 0.018 49 0.911 0.528 0.475 0.050 500.069 0.022 0.035 0.007 51 0.053 0.024 0.030 0.004 52 0.472 0.213 0.1260.027 53 >5 >5 >5 >5 55 >5 >5 >5 0.300 64 >5 >5 >5 >5 65 >5 >5 >5 >5 701.448 0.697 0.530 0.017 71 >5 >5 >5 >5 79 >5 1.066 >5 >5 80 0.461 0.0920.230 0.460 81 2.610 1.560 3.250 0.500 83 0.399 0.305 0.315 0.05584 >5 >5 >5 >5 85 >5 >5 >5 >5 86 >5 >5 >5 >5 87 >5 >5 >5 >5 88 0.4180.043 0.055 0.025 89 >5 >5 >5 >5 91 >5 >5 >5 0.070 93 >5 >5 >5 >5 94 >50.101 95 >5 0.310 96 6.365 1.108 1.550 >5 97 0.862 0.278 0.345 >5 980.442 0.157 0.140 1.050 99 1.810 1.012 0.410 >5 100 0.265 0.153 0.4150.035 102 3.130 3.590 4.500 0.165 103 >5 >5 >5 >5 104 >5 >5 >5 0.185 1060.350 0.440 107 1.728 1.950 1.650 0.019 108 2.425 2.035 3.050 0.067111 >5 >5 >5 >5 113 >5 >5 >5 3.000 114 >5 >5 >5 >5 115 0.094 0.022 0.0510.007 116 >5 >5 3.750 0.313 117 >5 >5 4.000 0.076 118 >5 >5 3.800 0.079119 >5 >5 >5 1.600 120 >5 >5 >5 1.900 121 >5 >5 >5 0.092

The compounds of this invention also are inhibitors of the growth factorreceptor tyrosine kinase enzymes, FGFr and PDGFr, and of the nonreceptortyrosine kinase enzyme, c-Src. Several of the invention compounds havebeen evaluated via standard assays that measure their ability to inhibittyrosine kinase enzymes. These assays are carried out as follows:

PDGF and FGF Receptor Tyrosine Kinase Assays

Full-length cDNAs for the mouse PDGF-β and human FGF-1 (flg) receptortyrosine kinases are obtained from J. Escobedo and prepared as describedin J. Biol. Chem. 1991; 262:1482-1487. PCR primers are designed toamplify a fragment of DNA that codes for the intracellular tyrosinekinase domain. The fragment is inserted into a baculovirus vector,cotransfected with AcMNPV DNA, and the recombinant virus isolated. SF9insect cells are infected with the virus to overexpress the protein, andthe cell lysate is used for the assay. Assays are performed in 96-wellplates (100 μL/incubation/well), and conditions are optimized to measurethe incorporation of ³²P from γ³²P-ATP into a glutamate-tyrosineco-polymer substrate. Briefly, to each well is added 82.5 μL ofincubation buffer containing 25 mM Hepes (pH 7.0), 150 mM NaCl, 0.1%Triton X-100, 0.2 mM PMSF, 0.2 mM Na₃VO₄, 10 mM MnCl₂, and 750 μg/mL ofPoly (4:1) glutamate-tyrosine followed by 2.5 μL of inhibitor and 5 μLof enzyme lysate (7.5 μg/μL FGF-TK or 6.0 μg/μL PDGF-TK) to initiate thereaction. Following a 10-minute incubation at 25° C. 10 mL of γ³²P-ATP(0.4 μCi plus 50 μM ATP) is added to each well, and samples areincubated for an additional 10 minutes at 25° C. The reaction isterminated by the addition of 100 μL of 30% trichloroacetic acid (TCA)containing 20 mM sodium pyrophosphate and precipitation of material ontoglass fiber mats (Wallac). Filters are washed 3 times with 15% TCAcontaining 100 mM sodium pyrophosphate, and the radioactivity retainedon the filters counted in a Wallac 1250 Betaplate reader. Nonspecificactivity is defined as radioactivity retained on the filters followingincubation of samples with buffer alone (no enzyme). Specific enzymaticactivity (enzyme plus buffer) is defined as total activity minusnonspecific activity. The % inhibition at 50 μM is determined, and forthe more potent compounds the concentration of the compound thatinhibited specific activity be 50% (IC₅₀) is determined based on theinhibition curve.

C-Src Kinase Assay

C-Src kinase is purified from baculovirus infected insect cell lysatesusing an antipeptide monoclonal antibody directed against the N-terminalamino acids (amino acids 2-17) of c-Src. The antibody, covalently linkedto 0.65 μm latex beads, is added to a suspension of insect cell lysisbuffer comprised of 150 mM NaCl, 50 mM Tris pH 7.5, 1 mM DTT, 1% NP-40,2 mM EGTA, 1 mM sodium vanadate, 1 mM PMSF, 1 μg/mL each of leupeptin,pepstatin, and aprotinin. Insect cell lysate containing c-Src protein isincubated with these beads for 3 to 4 hours at 4° C. with rotation. Atthe end of the lysate incubation, the beads are rinsed 3 times in lysisbuffer, resuspended in lysis buffer containing 10% glycerol, and frozen.These latex beads are thawed, rinsed 3 times in assay buffer (40 mMTris, pH 7.5, 5 mM MgCl₂), and suspended in the same buffer. In aMillipore 96-well plate with a 0.65 μm polyvinylidine membrane bottomare added the reaction components: 10 μL c-Src beads, 10 μL of 2.5 mg/mLpoly GluTyr substrate, 5 μM ATP containing 0.2 μCi labeled ³²P-ATP, 5 μLDMSO containing inhibitors or as a solvent control, and buffer to makethe final volume 125 μL. The reaction is started at room temperature byaddition of the ATP and quenched 10 minutes later by the addition of 125μL of 30% TCA, 0.1 M sodium pyrophosphate for 5 minutes on ice. Theplate is then filtered and the wells washed with two 250-mL aliquots of15% TCA, 0.1 M pyrophosphate. The filters are then punched, counted in aliquid scintillation counter, and the data examined for inhibitoryactivity in comparison to a known inhibitor such as erbstatin. Themethod is also described in J. Med. Chem., 1994; 37:598-609.

The tyrosine kinase inhibitors activity for representative inventioncompounds evaluated in the foregoing assays is given in Table 3.

TABLE 3 Inhibition of Tyrosine Kinases: % Inhibition at 50 μM (IC₅₀ [μM]in parenthesis if determined) Compound PDGFr FGFr 1 94.4 93.7 (0.593) 989.8 11 (0.131) (0.284) 45 21.9 67.4 46 17.5 19.5 47 10.5 55 (0.033)(0.151) 70 (0.536) (1.15) 80 18.6 117 (0.081) (0.061)

As noted above, the invention also provides pharmaceutical compositionscomprising an invention compound admixed with a carrier diluent, orexcipient. The following examples illustrate typical compositionsprovided by this invention.

EXAMPLE 144

A pharmaceutical compositions in the form of hard gelatin capsules fororal administration is prepared using the following ingredients.

Quantity (mg/capsule) Active compound 250 Starch powder 200 Magnesiumstearate 10 Total 460

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities. A typical active ingredient is1-isobutyl-3-[2-{(2-chloro-4-piperazin-1-yl)-phenylamino}-pyrido[2,3-d]pyrimidin-7-yl]-urea.The composition is administered from 2 to 4 times a day for treatment ofpostsurgical restenosis.

EXAMPLE 144a

Compositions for Oral Suspension Ingredient Amount1-Isopropyl-3-[5-methyl-6-bromo-2-(3-ethylpyridin-4- 500 mgylamino)-pyrido-[2.3-d]pyrimidin-7-yl]-urea Sorbitol solution (70% NF) 40 mL Sodium benzoate 150 mg Saccharin  10 mg Cherry flavor  50 mgDistilled water q.s. ad 100 mL

The sorbitol solution is added to 40 mL of distilled water, and thepyridopyrimidine is suspended therein. The saccharin, sodium benzoate,and flavoring are added and dissolved. The volume is adjusted to 100 mLwith distilled water. Each milliliter of syrup contains 5 mg of activeingredient.

EXAMPLE 144b

Tablets Each Containing 60 mg of Active Ingredient Active ingredient 60mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone(as 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mgMagnesium stearate 0.5 mg Talc 1.0 mg Total 150 mg

The active ingredient, starch, and cellulose are passed through a No. 45mesh US sieve and mixed thoroughly. The solution of polyvinylpyrrolidoneis mixed with the resultant powders and then passed through a No. 14mesh US sieve. The granules are dried at 50° C. to 60° C. and passedthrough a No. 18 mesh US sieve. The sodium carboxymethyl starch,magnesium stearate, and talc, previously passed through a No. 60 mesh USsieve, are then added to the granules which, after mixing, arecompressed on a tablet machine to yield tablets each weighing 150 mg.

A typical active ingredient utilized in the above preparation is thecompound of Example 40 (Compound 12). This composition is well-suited totreatment of diabetic retinopathy.

EXAMPLE 144c

A parenteral composition suitable for administration by injection isprepared by dissolving 100 mg of compound 77 in 250 mL of 0.9% aqueoussodium chloride solution and adjusting the pH of the solution to about7.0. This formulation is well-suited for the treatment of breast cancer.

EXAMPLE 144d

Preparation for Suppositories

A mixture of 500 mg of1-n-butyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-ureaand 1500 mg, of theobroma oil are blended to uniformity at 60° C. Themixture is cooled to 24° C. in tapered molds. Each suppository willweigh about 2 g and can be administered from 1 to 2 times each day fortreatment of viral infections such as herpes and HIV.

EXAMPLE 144e

Topical Preparation Amount Ingredient (mg)1-Cyclohexyl-3-{[2-(4-morpholin-1-yl-phenylamino)]-5,6- 20difluoro-pyrido[2.3-d[pyrimidin-7-yl}-urea Propylene glycol 100 WhitePetrolatum 500 Cetearyl alcohol 50 Glyceryl stearate 100 PEG 100stearate 100 Ceteth-20 50 Monobasic sodium phosphate 80 Total 1000

The invention compound is blended to uniformity with the otheringredients to make a thick suspension. The suspension is applied evenlyto an adhesive backed polymeric film and cut into a 2-inch square. Thepatch is applied to the skin of a patient suffering from psoriasis.

EXAMPLE 144f

Slow Release Preparation

Five hundred milligrams of7-acetamido-6-bromo-2-[4-(2-diethylaminoethoxy)-phenylamino]pyrido[2,3-d]pyrimidinehydrochloride was placed in an osmotic pump tablet and administeredorally to a subject for treatment and prevention of restenosis.

The invention and the manner and process of making and using it are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains to make and use the same.It is to be understood that the foregoing describes preferredembodiments of the present invention, and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as the invention, thefollowing claims conclude this specification.

1. A compound of the Formula I

and pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, wherein: R², R⁷, R¹³, R¹⁴, and R¹⁵ are independently hydrogen,or lower alkyl, lower alkenyl, lower alkynyl, or —(CH₂)_(n)R¹² each ofwhich is optionally substituted with up to 5 groups independentlyselected from halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹,—(CH₂)_(n)CO₂R⁹, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹, —COR⁹, —CONR⁹R¹⁰,—SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂,—NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or a heterocycleoptionally substituted with up to 3 groups independently selected from—R⁹, —NR⁹R¹⁰, —OR⁹, —NR⁹COR¹⁰, —COR¹⁰, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹;R⁵ is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, or —OR⁹; R⁶ is halogen,cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹, —CO₂R⁹, —COR⁹, —CONR⁹R¹⁰, —NR⁹COR¹⁰,—SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, or loweralkenyl or lower alkynyl optionally substituted with —R⁹; R⁸ is H,—CO₂R¹³, —COR¹³, —CONR¹³R¹⁴, —CSNR¹³R¹⁴, —C(NR¹³)NR¹⁴R¹⁵, —SO₃R¹³,—SO₂R¹³, —SO₂NR¹³R¹⁴, —PO₃R¹³R¹⁴, —POR¹³R¹⁴, or —PO(NR¹³R¹⁴)₂; R⁹ andR¹⁰ are independently hydrogen, or lower alkyl, optionally substitutedwith up to 3 groups selected from the group consisting of halogen,amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl andsubstituted phenyl, or when taken together with the nitrogen to whichthey are attached, R⁹ and R¹⁰ form a ring having from 3-7 members, up tofour of which may be selected from the group consisting of

 O, S, and NR²⁰, where R²⁰ is hydrogen, lower alkyl, or —CO lower alkyl;R¹¹ is a heteroaryl or a heterocyclic group; R¹² is a cycloalkyl, aheterocyclic, an aryl, or a heteroaryl group; and Each n isindependently 0, 1, 2, or
 3. 2. A compound of the Formula II

and pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, wherein: R⁷, R¹³, R¹⁴, and R¹⁵ are independently hydrogen, orlower alkyl, lower alkenyl, lower alkynyl, or —(CH₂)_(n)R¹² each ofwhich is optionally substituted with up to 5 groups independentlyselected from halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹,—(CH₂)_(n)CO₂R⁹, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹, —COR⁹, —CONR⁹R¹⁰,—SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂,—NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or a heterocycleoptionally substituted with up to 3 groups independently selected from—R⁹, —NR⁹R¹⁰, —OR⁹, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹; R⁵ is halogen,cyano, nitro, —R⁹, —NR⁹R¹⁰, or —OR⁹; R⁶ is halogen, cyano, nitro, —R⁹,—NR⁹R¹⁰, —OR⁹, —CO₂R⁹, —COR⁹, —CONR⁹R¹⁰, —NR⁹COR¹⁰, or lower alkenyl orlower alkynyl optionally substituted with —R⁹; R⁸ is H, —CO₂R¹³, —COR¹³,—CONR¹³R¹⁴, —CSNR¹³R¹⁴, —C(NR¹³)NR¹⁴R¹⁵, —SO₃R¹³, —SO₂R¹³, —SO₂NR¹³R¹⁴,—PO₃R¹³R¹⁴, —POR¹³R¹⁴, or —PO(NR¹³R¹⁴)₂; R⁹ and R¹⁰ are independentlyhydrogen, or lower alkyl, optionally substituted with up to 3 groupsselected from the group consisting of halogen, amino, mono- ordialkylamino, hydroxy, lower alkoxy, phenyl and substituted phenyl, orwhen taken together with the nitrogen to which they are attached, R⁹ andR¹⁰ form a ring having from 3-7 members, up to four of which may beselected from the group consisting of

 O, S, and NR²⁰, where R²⁰ is hydrogen, lower alkyl, or —CO lower alkyl;R¹¹ is a heteroaryl or a heterocyclic group; R¹² is a cycloalkyl, aheterocyclic, an aryl, or a heteroaryl group; each n is independently 0,1, 2, or 3; and R¹⁶, R¹⁷, and R¹⁸ are independently hydrogen, halogen,amino, mono- or dialkylamino, hydroxy, lower alkyl, lower alkoxy, cyano,nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, alkylcarbonyl, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹,—PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰,or —NR⁹SO₂R¹⁰; or R¹⁶ is a heterocyclic group containing from 3-7members, up to 2 of which members are heteroatoms selected from oxygenand nitrogen, wherein the heterocyclic group is unsubstituted orsubstituted with 1, 2, or 3 groups independently selected from the groupconsisting of halogen, hydroxy, lower alkyl, trifluoromethyl, loweralkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heteroarylsulfonyl, heteroarylsulfonylalkyl,heterocyclylalkyl, heterocyclylsulfonyl, and heterocyclylsulfonylalkyl.3. A compound of the Formula III

and pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, wherein: R² is hydrogen, or lower alkyl, lower alkenyl, loweralkynyl, or —(CH₂)_(n)R¹², each of which is optionally substituted withup to 5 groups independently selected from halogen, cyano, nitro, —R⁹,—NR⁹R¹⁰, —OR⁹, —(CH₂)_(n)CO₂R⁹, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹, —COR⁹,—CONR⁹R¹⁰, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰,—PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or aheterocycle optionally substituted with up to 3 groups independentlyselected from —R⁹, —NR⁹R¹⁰, —OR⁹, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹; R⁵ ishalogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, or —OR⁹; R⁶ is halogen, cyano,nitro, —R⁹, —NR⁹R¹⁰, —OR⁹, —CO₂R⁹, —COR⁹, —CONR⁹R¹⁰, —NR⁹COR¹⁰,—SO₂NR⁹R¹⁰, —SO₂R⁹, —SO₃R⁹, SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, orlower alkenyl or lower alkynyl optionally substituted with —R⁹; R⁹ andR¹⁰ are independently hydrogen, or lower alkyl, optionally substitutedwith up to 3 groups selected from the group consisting of halogen,amino, mono- or dialkylamino, hydroxy, lower alkoxy, phenyl andsubstituted phenyl, or when taken together with the nitrogen to whichthey are attached, R⁹ and R¹⁰ form a ring having from 3-7 members, up tofour of which may be selected from the group consisting of

 O, S, and NR²⁰, where R²⁰ is hydrogen, lower alkyl, or —CO lower alkyl;R¹¹ is a heteroaryl or a heterocyclic group; R¹² is a cycloalkyl, aheterocyclic, an aryl, or a heteroaryl group; each n is independently 0,1, 2, or 3; R¹⁹ is hydrogen, or (i) lower alkyl, lower alkenyl, or loweralkynyl, each of which is optionally substituted with up to 5 groupsindependently selected from halogen, amino, mono- or dialkylamino,hydroxy, lower alkoxy, cyano, nitro, carboxy, carboxyalkyl,aminocarbonyl, mono- or dialkylaminocarbonyl, lower alkylcarbonyl,—SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂,—NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or (ii) aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl or cycloalkyl-alkyl,where each aryl, heteroaryl or cycloalkyl group is optionallysubstituted with up to 5 groups independently selected from halogen,amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro,carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl,alkylcarbonyl, —SO₃R⁹, —SO₂R⁹R¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰,—POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰,or (iii) a (CH₂)_(n)— heterocyclic group containing from 3-7 members, upto 2 of which members are heteroatoms selected from oxygen and nitrogen,wherein the heterocyclic group is unsubstituted or substituted with 1,2, or 3 groups independently selected from the group consisting ofhalogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino,mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heteroarylsulfonyl, heteroarylsulfonylalkyl, heterocyclylalkyl,heterocyclylsulfonyl, and heterocyclylsulfonylalkyl; and R²¹ ishydrogen, lower alkyl, or lower alkyl substituted with phenyl orsubstituted phenyl.
 4. A compound of the Formula IV

and pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, wherein: R⁵ is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, or —OR⁹; R⁶is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹, —CO₂R⁹, —COR⁹, —CONR⁹R¹⁰,—NR⁹COR¹⁰, —SO₂R⁹R¹⁰, —SO₂R⁹, —SO₃R⁹, —SR⁹, —PO₃R⁹R¹⁰, POR⁹R¹⁰,—PO(NR⁹R¹⁰)₂, or lower alkenyl or lower alkynyl optionally substitutedwith —R⁹; R⁹ and R¹⁰ are independently hydrogen, or lower alkyloptionally substituted with up to 3 groups selected from the groupconsisting of halogen, amino, mono- or dialkylamino, hydroxy, loweralkoxy, phenyl and substituted phenyl, or when taken together with thenitrogen to which they are attached, R⁹ and R¹⁰ form a ring having from3-7 members, up to four of which may be selected from

 O, S, and NR²⁰, where R²⁰ is hydrogen, lower alkyl, or —CO lower alkyl;R¹¹ is heteroaryl or a heterocyclic group; R¹⁶, R¹⁷, and R¹⁸ areindependently selected from halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰,—OR^(9, —(CH) ₂)_(n)CO₂R⁹, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹, —COR⁹,—CONR⁹R¹⁰, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰,—PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or aheterocycle optionally substituted with up to 3 groups independentlyselected from —R⁹, —NR⁹R¹⁰, —OR⁹, —NR⁹COR¹⁰, —COR¹⁰, —(CH₂)_(n)SO₂R¹¹,—(CH₂)_(n)R¹¹; R¹⁹ is hydrogen, or (i) lower alkyl, lower alkenyl, orlower alkynyl, each of which is optionally substituted with up to 5groups independently selected from halogen, amino, mono- ordialkylamino, hydroxy, lower alkoxy, cyano, nitro, carboxy,carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, loweralkylcarbonyl, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰,—PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or (ii)aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl orcycloalkyl-alkyl, where each aryl, heteroaryl or cycloalkyl group isoptionally substituted with up to 5 groups independently selected fromhalogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano,nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, alkylcarbonyl, —SO₃R⁹, —SO₂R⁹R¹⁰, —SO₂NR⁹R¹⁰,—SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰,—NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or (iii) a (CH₂)_(n)— heterocyclic groupcontaining from 3-7 members, up to 2 of which members are heteroatomsselected from oxygen and nitrogen, wherein the heterocyclic group isunsubstituted or substituted with 1, 2, or 3 groups independentlyselected from the group consisting of halogen, hydroxy, lower alkyl,trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl,heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl, andheterocyclylsulfonylalkyl; and R²¹ is hydrogen, lower alkyl, or loweralkyl substituted with phenyl or substituted phenyl.
 5. A compound ofthe Formula V

and the pharmaceutically acceptable salts, esters, amides, and prodrugsthereof; wherein: R⁵ is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, or —OR⁹; R⁶is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹, —CO₂R⁹, —COR⁹, —CONR⁹R¹⁰,—NR⁹COR¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SO₃R⁹, SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰,—PO(NR⁹R¹O)₂, or lower alkenyl or lower alkynyl optionally substitutedwith —R⁹; R¹⁶, R¹⁷, and R¹⁸ are independently selected from hydrogen,halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹, —(CH₂)_(n)CO₂R⁹,—(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹, —COR⁹, —CONR⁹R¹⁰, —SO₃R⁹, —SO₂NR⁹R¹⁰,—SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰,—NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or a heterocycle optionally substituted withup to 3 groups independently selected from —R⁹, —NR⁹R¹⁰, —OR⁹,—NR⁹COR¹⁰, —COR¹⁰, —(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹; R⁹ and R¹⁰ areindependently hydrogen, or lower alkyl optionally substituted with up to3 groups selected from the group consisting of halogen, amino, mono- ordialkylamino, hydroxy, lower alkoxy, phenyl and substituted phenyl, orwhen taken together with the nitrogen to which they are attached, R⁹ andR¹⁰ form a ring having from 3-7 members, up to four of which may beselected from the group consisting of

 O, S, and NR²⁰, where R²⁰ is hydrogen, lower alkyl, or —CO lower alkyl;R¹¹ is heteroaryl or a heterocyclic group; R¹⁹ is hydrogen, or (i) toweralkyl, lower alkenyl, or tower alkynyl, each of which is optionallysubstituted with up to 5 groups independently selected from halogen,amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano, nitro,carboxy, carboxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl,lower alkylcarbonyl, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰,—POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰,or (ii) aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl orcycloalkyl-alkyl, where each aryl, heteroaryl or cycloalkyl group isoptionally substituted with up to 5 groups independently selected fromhalogen, amino, mono- or dialkylamino, hydroxy, lower alkoxy, cyano,nitro, carboxy, carboxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, alkylcarbonyl, —SO₃R⁹, —SO₂R⁹R¹⁰, —SO₂NR⁹R¹⁰,—SO₂R⁹, —SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰,—NR⁹CONR⁹R¹⁰, —NR⁹SO₂R¹⁰, or (iii) a (CH₂)_(n)— heterocyclic groupcontaining from 3-7 members, up to 2 of which members are heteroatomsselected from oxygen and nitrogen, wherein the heterocyclic group isunsubstituted or substituted with 1, 2, or 3 groups independentlyselected from the group consisting of halogen, hydroxy, lower alkyl,trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heteroarylsulfonyl,heteroarylsulfonylalkyl, heterocyclylalkyl, heterocyclylsulfonyl, andheterocyclylsulfonylalkyl; and R²¹ is hydrogen, lower alkyl, or loweralkyl substituted with phenyl or substituted phenyl.
 6. A compound ofFormula VI

and the pharmaceutically acceptable salts, esters, amides, and prodrugsthereof; wherein: R⁵ is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, or —OR⁹; R⁶is halogen, cyano, nitro, —R⁹, —NR⁹R¹⁰, —OR⁹, —CO₂R⁹, —COR⁹, —CONR⁹R¹⁰,—NR⁹COR¹⁰, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SO₃R⁹, SR⁹, —PO₃R⁹R¹⁰, —POR⁹R¹⁰,—PO(NR⁹R¹⁰)₂, or lower alkenyl or lower alkynyl optionally substitutedwith —R⁹; R¹⁷ and R¹⁸ are independently selected from halogen, cyano,nitro, —R⁹, —NR⁹R¹⁰, —OR⁹, —(CH₂)_(n)CO₂R⁹, —(CH₂)_(n)SO₂R¹¹,—(CH₂)_(n)R¹¹, —COR⁹, —CONR⁹R¹⁰, —SO₃R⁹, —SO₂NR⁹R¹⁰, —SO₂R⁹, —SR⁹,—PO₃R⁹R¹⁰, —POR⁹R¹⁰, —PO(NR⁹R¹⁰)₂, —NR⁹COR¹⁰, —NR⁹CO₂R¹⁰, —NR⁹CONR⁹R¹⁰,—NR⁹SO₂R¹⁰, or a heterocycle optionally substituted with up to 3 groupsindependently selected from —R⁹, —NR⁹R¹⁰, —OR⁹, —NR⁹COR¹⁰, —COR¹⁰,—(CH₂)_(n)SO₂R¹¹, —(CH₂)_(n)R¹¹; and R²² and R²³ independently arehydrogen or alkyl.
 7. A compound selected from:1-tert-Butyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-tert-Butyl-3-[2-(3-chloro-4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-tert-Butyl-3-[6-fluoro-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-tert-Butyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-3-chloro-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-tert-butyl-urea;1-Cyclohexyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-[2-(3-Chloro-4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-cyclohexyl-urea;1-Cyclohexyl-3-[6-fluoro-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-3-chloro-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea;1-(2-Hydroxy-ethyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-[2-(3-Chloro-4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(2-hydroxy-ethyl)-urea;1-[6-Fluoro-2-(4-piperazin-1-yl)-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(2-hydroxy-ethyl)-urea;1-(2-Hydroxy-ethyl)-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-hydroxy-ethyl)-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-3-chloro-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-hydroxy-ethyl)-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-hydroxy-ethyl)-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-hydroxy-ethyl)-urea;1-Ethyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-[2-(3-Chloro-4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-ethyl-urea;1-Ethyl-3-[6-fluoro-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Ethyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-ethyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-3-chloro-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-ethyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-3-ethyl-urea;1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-ethyl-urea;1-tert-Butyl-3-(2-phenylamino-pyrido[2,3-d]pyrimidin-7-yl)-urea;1-tert-Butyl-3-[2-(4-fluoro-3-methyl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-(4-Chloro-phenyl)-3-[2-(4-fluoro-3-methyl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Isopropyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-tert-Butyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-Cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-Cyclopentyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-Cyclopentyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[6-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[6-bromo-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[6-cyano-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[6-chloro-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[6-fluoro-5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[6-bromo-5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[6-chloro-5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Isopropyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Ethyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-[5-Methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Methyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-1-methyl-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-(4-Hydroxy-cyclohexyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-(4-Amino-cyclohexyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-(2-Dimethylamino-ethyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-(3-Morpholino-4-yl-propyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;3-Cyclohexyl-1-methyl-1-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;N,N-Dimethyl-N□-[5-methyl-2-[[4-(1-piperazinyl)phenyl]-amino]-pyrido[2,3-d]pyrimidin-7-yl]-sulfamide;1-Cyclohexyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-thiourea;N-[2-(4-Piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-acetamide;4-[7-(3-Cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-benzenesulfonamide;1-Cyclohexyl-3-{2-[4-(1-piperazin-1-yl-methanoyl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-Cyclohexyl-3-[2-(4-fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-(2-{4-[4-(2-Amino-4-methyl-pentanoyl)-piperazin-1-yl]-phenylamino}-pyrido[2,3-d]pyrimidin-7-yl)-3-cyclohexyl-urea;and1-(2-{4-[4-(2-Amino-3-methyl-butanoyl)-piperazin-1-yl]-phenylamino}-pyrido[2,3-d]pyrimidin-7-yl)-3-cyclohexyl-urea.8. A compound selected from:1-tert-Butyl-3-[2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Ethyl-3-[2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-(Hydroxy-ethyl)-3-[2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-tert-Butyl-3-[6-fluoro-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[6-fluoro-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Ethyl-3-[6-fluoro-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-[6-Fluoro-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(2-hydroxy-ethyl)-urea;1-tert-Butyl-3-[5-methyl-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-[5-methyl-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Ethyl-3-[5-methyl-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;and1-(2-Hydroxy-ethyl)-3-[5-methyl-2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea.9. A compound selected from:4-{4-[7-(3-tert-Butyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester;4-{4-[7-(3-Cyclohexyl-ureido)-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester;1-(3-Hydroxy-propyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-((S)-1-Hydroxymethyl-3-methyl-butyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;4-Methyl-piperazine-1-carboxylic acid[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-amide;Piperazine-1-carboxylic acid[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-amide;1-((R)-1-Hydroxymethyl-2-methyl-propyl)-3-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-[6-Bromo-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-tert-butyl-urea;1-{6-Bromo-2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-cyclohexyl-urea;1-[2-(4-Fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(3-morpholin-4-yl-propyl)-urea;1-[2-(4-Fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-(2-hydroxy-ethyl)-urea;1-(2-Amino-ethyl)-3-[2-(4-fluoro-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-Cyclohexyl-3-{2-[4-(3,3-dimethyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-tert-Butyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-fluoro-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-tert-Butyl-3-{6-chloro-2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea;3-Cyclohexyl-1-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-1-methyl-urea;3-Cyclohexyl-1-ethyl-1-[2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;3-tert-Butyl-1-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-1-ethyl-urea;7-(3-tert-Butyl-ureido)-2-(4-piperazin-1-yl-phenylamino)-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester;1-Cyclohexyl-3-{2-[4-(3,3-dimethyl-piperazin-1-yl)-phenylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-Cyclohexyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-methyl-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-tert-Butyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-methyl-pyrido[2,3-d]pyrimidin-7-yl}-urea;1-tert-Butyl-3-[6-methyl-2-(4-piperazin-1-yl)-phenylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea;1-{2-[4-(cis-3,5-Dimethyl-piperazin-1-yl)-phenylamino]-6-methyl-pyrido[2,3-d]pyrimidin-7-yl}-3-isopropyl-urea;1-Cyclopropyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-methyl-pyrido[2,3-d]pyrimidin-7-yl}-urea;and1-tert-Butyl-3-{2-[4-(cis-3,5-dimethyl-piperazin-1-yl)-phenylamino]-6-ethyl-pyrido[2,3-d]pyrimidin-7-yl}-urea.10. A pharmaceutical composition comprising a compound selected fromclaim 1 admixed with a pharmaceutically acceptable carrier, diluent, orexcipient.
 11. A method of inhibiting a cdk enzyme comprising contactingthe cdk enzyme with a compound selected from claim
 1. 12. A method ofclaim 11 wherein said cdk is cdk1.
 13. A method of claim 11 wherein saidcdk is cdk2.
 14. A method of claim 11 wherein said cdk is cdk4.
 15. Amethod of inhibiting a growth factor-mediated tyrosine kinase comprisingcontacting said growth factor-mediated kinase with a compound selectedfrom claim
 1. 16. A method of claim 15 wherein said growthfactor-mediated tyrosine kinase is platelet derived growth factor(PDGF).
 17. A method of claim 15 wherein said growth factor-mediatedtyrosine kinase is fibroblast growth factor (FGF).
 18. A method oftreating a subject suffering from diseases caused by vascular smoothmuscle cell proliferation comprising administering to said subject atherapeutically effective amount of a compound selected from claim 1.